review article stem cells applications in...

Review ArticleStem Cells Applications in Regenerative Medicine andDisease Therapeutics

Ranjeet Singh Mahla

Department of Biological Sciences Indian Institute of Science Education and Research (IISER)Bhopal Madhya Pradesh 462066 India

Correspondence should be addressed to Ranjeet Singh Mahla ranjeetiiserbacin

Received 13 March 2016 Accepted 5 June 2016

Academic Editor Paul J Higgins

Copyright copy 2016 Ranjeet Singh MahlaThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Regenerative medicine the most recent and emerging branch of medical science deals with functional restoration of tissues ororgans for the patient suffering from severe injuries or chronic disease The spectacular progress in the field of stem cell researchhas laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines The indefiniteself-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicineThe transdifferentiating potential of stem cells varies with source and according to that regenerative applications also changeAdvancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3Dorganoids and tissue structures for personalized applicationsThis review outlines the most recent advancement in transplantationand tissue engineering technologies of ESCs TSPSCs MSCs UCSCs BMSCs and iPSCs in regenerative medicine Additionallythis review also discusses stem cells regenerative application in wildlife conservation

1 Introduction

Regenerativemedicine themost recent and emerging branchof medical science deals with functional restoration ofspecific tissue andor organ of the patients suffering withsevere injuries or chronic disease conditions in the statewhere bodies own regenerative responses do not suffice [1]In the present scenario donated tissues and organs cannotmeet the transplantation demands of aged and diseasedpopulations that have driven the thrust for search for thealternatives Stem cells are endorsed with indefinite celldivision potential can transdifferentiate into other types ofcells and have emerged as frontline regenerative medicinesource in recent time for reparation of tissues and organsanomalies occurring due to congenital defects disease andage associated effects [1] Stem cells pave foundation for all tis-sue and organ system of the body andmediates diverse role indisease progression development and tissue repair processesin host On the basis of transdifferentiation potential stemcells are of four types that is (1) unipotent (2) multipotent(3) pluripotent and (4) totipotent [2] Zygote the onlytotipotent stem cell in human body can give rise to whole

organism through the process of transdifferentiation whilecells from inner cells mass (ICM) of embryo are pluripotentin their nature and can differentiate into cells representingthree germ layers but do not differentiate into cells ofextraembryonic tissue [2] Stemness and transdifferentiationpotential of the embryonic extraembryonic fetal or adultstem cells depend on functional status of pluripotency fac-tors like OCT4 cMYC KLF44 NANOG SOX2 and soforth [3ndash5] Ectopic expression or functional restoration ofendogenous pluripotency factors epigenetically transformsterminally differentiated cells into ESCs-like cells [3] knownas induced pluripotent stem cells (iPSCs) [3 4] On the basisof regenerative applications stem cells can be categorized asembryonic stem cells (ESCs) tissue specific progenitor stemcells (TSPSCs) mesenchymal stem cells (MSCs) umbilicalcord stem cells (UCSCs) bone marrow stem cells (BMSCs)and iPSCs (Figure 1 Table 1)The transplantation of stem cellscan be autologous allogenic and syngeneic for induction oftissue regeneration and immunolysis of pathogen or malig-nant cells For avoiding the consequences of host-versus-graft rejections tissue typing of human leucocyte antigens(HLA) for tissue and organ transplant as well as use of

Hindawi Publishing CorporationInternational Journal of Cell BiologyVolume 2016 Article ID 6940283 24 pageshttpdxdoiorg10115520166940283

2 International Journal of Cell Biology

Healthy donor

Patient

(1) ESCs (2) TSPSCs (3) MSCs (4) UCSCs(5) BMSCs (6) IPSCs

Promises of stem cells in regenerative medicines

(1)

(2)

(3)

(4)

(5)

(6)

(i) T1DM and T2DM treatment(ii) SLE (autoimmune disease) treatment

(iii) Application for HI treatment(iv) Krabbersquos disease treatment(v) Hematopoiesis in neuroblastoma

(i) Improvement of spinal cord injury(ii) Regeneration of retinal sheet

(iii) Generation of retinal ganglion cells(iv) Healing of heart defects(v) Hepatic cell formation

(vii) Cartilage lesion treatment(viii) Regeneration of pacemaker

(ix) In vitro gametogenesis

(i) Regeneration of kidney tissue(ii) Vision restoration in AMD(iii) Treatment of placental defects (iv) Treatment of brain cortex defects(v) ASD and autism treatment

(vi) Treatment of liver and lung disease(vii) Generation of serotonin neurons(viii) Regeneration of pacemaker

(i) Treatment of diabetes and retinopathy (ii) Neurodental therapeutic applications

(iii) Restoration of cognitive functions(iv) Brain and cancer treatment (v) Ear acoustic function restoration

(vi) Regeneration of intestinal mucosa (vii) Treatment of vision defects

(viii) Muscle regeneration(ix) Regeneration of fallopian tube

(i) Regeneration of bladder tissue(ii) Muscle regeneration

(iii) Regeneration of teeth tissue(iv) Healing of orthopedic injuries (v) Recovery from muscle injuries

(vi) Hear scar repair after attack

(i) Treatment of anemia and blood cancer(ii) Retroviral therapy

(iii) Correction of neuronal defects(iv) Generation of functional platelets(v) Alveolar bone regeneration

(vi) Regeneration of diaphragm tissue

(vi) Formation of insulin secreting 120573-cells

Figure 1 Promises of stem cells in regenerative medicine the six classes of stem cells that is embryonic stem cells (ESCs) tissue specificprogenitor stem cells (TSPSCs) mesenchymal stem cells (MSCs) umbilical cord stem cells (UCSCs) bone marrow stem cells (BMSCs) andinduced pluripotent stem cells (iPSCs) have many promises in regenerative medicine and disease therapeutics

immune suppressant is recommended [6] Stem cells expressmajor histocompatibility complex (MHC) receptor in lowand secret chemokine that recruitment of endothelial andimmune cells is enabling tissue tolerance at graft site [6]The current stem cell regenerative medicine approaches arefounded onto tissue engineering technologies that combinethe principles of cell transplantation material science andmicroengineering for development of organoid those canbe used for physiological restoration of damaged tissue andorgans The tissue engineering technology generates nascenttissue on biodegradable 3D-scaffolds [7 8]The ideal scaffoldssupport cell adhesion and ingrowths mimic mechanics oftarget tissue support angiogenesis and neovascularisationfor appropriate tissue perfusion and being nonimmuno-genic to host do not require systemic immune suppres-sant [9] Stem cells number in tissue transplant impactsupon regenerative outcome [10] in that case prior ex vivoexpansion of transplantable stem cells is required [11] Forsuccessful regenerative outcomes transplanted stem cellsmust survive proliferate and differentiate in site specific

manner and integrate into host circulatory system [12] Thisreview provides framework of most recent (Table 1 Figures1ndash8) advancement in transplantation and tissue engineeringtechnologies of ESCs TSPSCs MSCs UCSCs BMSCs andiPSCs in regenerativemedicine Additionally this review alsodiscusses stem cells as the tool of regenerative applications inwildlife conservation

2 ESCs in Regenerative Medicine

For the first time in 1998 Thomson isolated human ESCs(hESCs) [13] ESCs are pluripotent in their nature and cangive rise to more than 200 types of cells and promises forthe treatment of any kinds of disease [13] The pluripo-tency fate of ESCs is governed by functional dynamics oftranscription factors OCT4 SOX2 NANOG and so forthwhich are termed as pluripotency factors The two allelesof the OCT4 are held apart in pluripotency state in ESCsphase through homologues pairing during embryogenesis

International Journal of Cell Biology 3Ta

ble1Ap

plicationof

stem

cells

inregenerativ

emedicineste

mcells

(ESC

sTS

PSCs

MSC

sUCS

CsB

MSC

sandiPSC

s)have

diverseapplications

intissueregeneratio

nanddisease

therapeutic

s

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

ESCs

Spinalcord

injurie

sInfection

cancerand

accidents

ESCs

transplantationto

injury

site

ESCs

andsecreted

vasculogenicand

neurogenicfactor

supp

orttissue

homing

Regeneratio

nof

spinaltissuea

ndim

proved

balancea

ndsensation

[15]

ARM

Dand

glaucoma

Macular

cones

degeneratio

n

ESCs

-derived

conesa

ndRG

Cstransplantationto

eye

COCO

(activatingTG

F-120573B

MPand

Wnt)amp

BRN3(kno

ck-in

byCR

ISPE

R-Ca

s9)m

akeE

SCsb

ecom

econesa

ndRG

Csform

cells

sheetamp

neuron

alconn

ectio

n

Recovery

from

ARM

Dandmacular

defectsamp

resto

ratio

nof

visio

n[1617]

Cardiovascular

disease

Diabetesdrugs

genetic

factor

andlifes

tyle

ESCs

-derived

CMsamp

biom

aterialcoaxedES

Cs

Cardiomyocytese

xpressGCa

MP3

secretingvasculogenicfactorsandTb

ox3

differentiatesE

SCsintoSA

NPC

s

Supp

resses

heartarrhythmiasCM

sele

ctroph

ysiologically

integratetoheart

aspacemaker

[181928]

Liverinjuries

Toxinsdrugs

genetic

factors

andinfection

Transplantationof

ESCs

-derived

hepatocytes

ESCs

-hepatocytec

onversionismarked

with

expressio

nof

Cytp450PX

RCY

PA4amp

29H

NF4

-120572and

UGTA

1cells

intransplant

repo

pulateinjured

liver

tissue

Regeneratio

nof

liver

tissuec

anbe

used

asmod

elforscreening

ofdrugs

[202324]

Diabetes

Lifesty

leheart

defectsand

genetic

s

Transplantationof

ESCs

-derived

PPCs

Progenito

rs(C

D24+

CD49+

ampCD

133+)

differentiateinto120573-cells

secreteinsulin

andexpressP

DX1G

CKand

GLU

T2

Improvem

entinglucoselevelandob

esity

canbe

used

fortreatmento

fT1D

Mand

T2DM

[2526]

Oste

oarthritis

Whencartilage

tissuew

ears

away

Transplantationof

chon

drocytes

organo

ids

Chon

drocytes

(SOX9+

ampcollagen-II+

)form

cells

aggregateamp

remainactiv

efor

12wks

attransplantationsite

Regeneratio

nof

cartilage

tissuec

anbe

used

fortreatmento

finjuriesfaced

byathletes

[27]

TSPS

Cs

Diabetes

Lifesty

leand

genetic

factors

Transplantationof

SCs

deriv

edPP

Csorgano

idPP

Csneed

niches

uppo

rted

activ

eFGFamp

Notch

signalling

tobecome120573

-cell

PPCs

occupancyas120573-cellcan

treatT1DM

ampT2

DM

[252930]

Neurodental

prob

lems

Accidentsage

andgenetic

factors

Transplantationof

DSP

SCsa

sneurons

Neurons

expressn

estin

GFA

P120573III-tubu

linand

L-type

Ca2+

channels

Possibleapplicationin

treatmento

fneurod

entalabn

ormalities

[3132]

Acou

sticp

roblem

sAgenoise

drugsand

infection

IESC

sIESC

s-deriv

edhaircells

transplantation120574-secretase

shutsN

otch

by120573-catenin

ampAtoh

1inlrg

5+IESC

stobe

haircells

Cochlearregenerationleadsto

resto

ratio

nof

acou

sticfunctio

ns[3435]

Intestinal

degeneratio

n

Geneticfactors

andfood

borne

infections

IPCs

deriv

edcrypt-v

illi

organo

idtransplantation

M120601m

yofib

roblasts

andbacteriasig

nals

IPCs

tobe

crypt-v

illiorganoidtissue

Regeneratio

nof

gobletmucosac

antre

atintestinaldefects

[36ndash

38]

Cornealdiseases

Burnsgenetic

sand

inflammation

LPSC

stransplantatio

nto

cornealtissue

LPSC

sintransplant

markedby

ABC

B5differentiateinto

maturec

ornea

Regeneratio

nof

cornealtissue

might

treat

multip

leeyed

isease

[3940

]

Muscular

deform

ities

Infection

drugs

and

autoim

mun

ity

Transplantationof

PEG

fibrin

ogen

coaxed

MABs

PDGFfro

mMABs

attractvasculogenic

andneurogeniccells

totransplant

site

Muscle

fibril

regeneratio

nskeletal

muscle

defectstreatment

[4142]

Eyed

iseaseamp

retin

opathy

Toxinsburns

andgenetic

factors

AdSC

sintravitre

altransplantation

AdSC

sfrom

healthydo

norp

rodu

cehigh

ervasoprotectiv

efactors

Resto

ratio

nof

vascularisa

tion

diabetic

retin

opathy

treatment

[4445]

Cardiac

dysfu

nctio

ns

Agegenetic

factorsand

toxins

Syste

micinfusio

nof

CA-AdS

Csmyocardium

CA-AdS

Csto

epith

elium

differentiatio

nares

uperiortoAd

SCs

Regeneratio

nof

ischemicmyocardium

[4748]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

MSC

s

Bladder

deform

ities

Cystitiscancer

andinfection

Transplantationof

BD-M

SCstobladder

BDMSC

s(CD

105+C

D73+

CD34minus

and

CD45minus

)with

SIShealbladderin10wks

Bladderregenerationfro

mdifferent

originsM

SCs

[5051]

Dentalproblem

sInfection

cancer

ageand

accidents

Transplantso

fEMSC

s+DSC

sbiopo

lymer

tissue

EMSC

-DSC

sand

vasculogenicfactorsin

biop

olym

ergive

risetomatureteeth

units

Regeneratio

nof

oraltissuea

ndapplicationin

perio

dontics

[3152]

Bone

degeneratio

nInjurie

sand

tumor

autoim

mun

ity

CoaxedMSC

stransplant

ampMSC

sinfusion

Actin

mod

ellin

gby

cytochalasin-D

transfo

rmsM

SCsintoosteob

lasts

Regeneratio

nof

bonesredu

ctionin

injury

pain

[53ndash55]

Muscle

degeneratio

nGeneticfactors

andworkstr

ess

CoaxedMSC

stransplant

andMSC

sinfusion

Alginateg

elprotectsMSC

sfrom

immun

eattack

andcontrolsGFs

release

Regeneratio

nof

heartscara

ndmuscle

tissueincontrolledway

[5657]

Alopecia

Agedise

ase

andmedicine

use

Transplantationof

GAG

-coatedDPC

s

GAG

coatingmim

icsE

CMmicroenvironm

entprom

otingDPC

sregeneratio

n

Regeneratio

nof

hairfollicle

fortreatment

ofalop

ecia

[58]

UCS

Cs

Con

genitalh

eart

defects

Develo

pmental

errors

Transplantationof

fibrin

coaxed

AFS

CsAd

ditio

nof

VEF

Gto

PEGcoaxed

AFS

Csprom

otes

organo

genesis

Regeneratio

nof

tissuer

epairfor

treatmento

fheartdefects

[5960]

Diabetes

Lifesty

leand

genetic

factors

WJ-SC

stransplantation

andintravenou

sinjection

WJ-factorsamp

M120601differentiateWJ-SC

sinto120573-cells

decreasin

gIL6ampIL1120573

Improvem

entinfunctio

nof120573-cellsleads

totre

atmento

fdiabetes

[7961ndash63]

SLE

Autoim

mun

ityIntravenou

sinfusionof

WJ-SC

sWJ-SC

sdecreaseS

LEDAIamp

BILA

G

reinfusio

nprotectsfro

mdiseaser

elapse

Improvem

entinrenalfun

ctions

ampsto

ppingdegeneratio

nof

tissues

[64]

LSDamp

neurod

egenerative

diseases

Geneticstumor

ageandlife

style

Allo

genicU

CSCs

cells

andbiom

aterialcoaxed

UCS

Csorgano

ids

Organoids

consisted

ofneurob

lasts

(GFA

P+N

estin+

and

Ki67+

)ampSC

s(O

CT4+SOC2+

)UCS

Csrecoverfrom

MSE

deficiencyandim

provec

ognitio

n

Treatm

ento

fKrabb

ersquosdiseasehu

rler

synd

romeMLD

TSD

ALD

ADA

LS

SCISC

ITB

IParkinsonsstr

okeandso

forth

[65ndash67]

Cartilage

and

tend

oninjurie

sAc

cident

Transplantationof

UCB

-SCs

UCB

-SCs

-HA

gel

HAgelfactorsprom

oter

egenerationof

hyalinec

artilageamp

tend

onsinwks

time

Recovery

from

tend

onsa

ndcartilage

injurie

s[6869]

Hod

gkinrsquos

lymph

oma

Geneticand

environm

ental

Transplantationof

UCS

CsSecond

dose

infectionof

allogenic

UCS

Csim

proves

patie

ntslife

by30

Treatm

ento

fHod

gkinrsquoslymph

omaa

ndotherc

ancers

[10]

Periton

ealfi

brosis

Long

term

renal

dialysisand

fibrosis

WJ-SC

stransplantation

byIP

injection

WJ-SC

sprevent

programmed

cells

death

andperiton

ealw

allthickness

Effectiv

eintre

atmento

fencapsulatin

gperiton

ealfi

brosis

[70]

International Journal of Cell Biology 5

Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

BMSC

s

Anaem

iaand

bloo

dcancer

Injurygenetics

autoim

mun

ityTw

o-ste

pinfusio

nof

lymph

oidandmyeloid

Haploidentic

alBM

SCsc

anreconstruct

immun

ityw

hich

ismajor

processfor

minority

Treatm

ento

faplastic

anaemiaamp

haem

atologicalmalignancies

[71]

AID

SHIV

1infectio

nTransplantationof

HIV

1resistant

CD4+

cells

Anti-H

IV1C

D4+

cells

expressH

IV1

anti-RN

Aw

hich

restric

tHIV

infection

Treatm

ento

fAID

Sas

analternativeo

fantiretroviral

[7273]

Bloo

dclo

tting

disorders

Lack

ofplatele

tsTransplantationof

megakaryocyte

organo

ids

GFs

insilkspon

gem

icrotubu

le3D

scaffolds

mim

icbo

nemarrow

Therapeutic

sofb

urns

andbloo

dclo

tting

diseases

[7475]

Neurodegenerativ

ediseases

Accidentsage

traumaand

stroke

Focaltransplanto

fBM

SCsw

ithLA

LA+

BMSC

sind

ucen

eovascularisa

tion

thatdirectsm

icrogliaforc

olon

ization

Treatm

ento

fneuronald

amaged

isorders

andcogn

itive

resto

ratio

n[76]

Orodental

deform

ities

Traumadisease

andbirthdefects

Bone

marrowderiv

edste

mampprogenito

r(TRC

)

CD14+

ampCD

90+

TRCacceleratealveolar

jawbo

neregeneratio

nRe

generatio

nof

defectsinoralbo

neskin

andgum

[77]

Diaph

ragm

abno

rmalities

Accidentsamp

birthdefects

Implantatio

nof

decellu

lariz

eddiaphragm

BMSC

sniche

perfused

hemidiaph

ragm

hassim

ilarm

yography

ampspiro

metry

Replacem

enttherapy

bydo

nord

erived

niched

diaphragm

[8]

iPSC

s

Eyed

efects

Agegenetics

andbirthdefects

iPSC

sderived

NPC

stransplantation

NPC

sform

5-6layersof

photoreceptor

nucle

iresto

ringvisualacuity

Treatm

ento

fARM

Dandother

age-related

eyed

efects

[78ndash80]

Neurodegenerativ

edisorders

Accidentsage

traumaand

stroke

iGABA

-INsa

ndcortical

spheroid

transplantation

(iGABA

-INs)secreteG

ABA

FOX1G

causeA

SDsph

eroidmim

icstobrain

ASD

Alzh

eimersseizerand

obstinate

epilepsiestreatment

[81ndash84]

Liveramp

lung

diseases

A1A

Ddeficiency

Transplantationof

A1A

Dmutationcorrected

iPSC

s

A1A

Disencodedby

SERP

INA1inliver

andmutationleadstodrugssensitivity

Treatm

ento

fCOPD

causinglung

sand

liver

degeneratio

n[85]

Diabetes

Lifesty

leand

genetic

factors

iPSC

sderived120573-cells

transplantation

Skin

to120573-cellsreprogrammingph

ase

throug

hcD

EampcPFrequ

iresG

PsTreatm

ento

fT1D

MandT2

DM

and

insulin

prod

uctio

n[86]

Lung

degeneratio

nTu

berculosis

cancerand

fibrosis

Biom

aterialcoaxed

iPSC

stransplantatio

nMiniature

iPSC

slun

gresembles

airw

ays

andalveolimod

eldrug

testing

Regeneratio

nof

lung

tissue

[87]

SIDsa

ndAID

SAgegenetic

factorsand

infection

Transplantationof

Oct4

andNanog

corrected

iPSC

s

CRISPE

R-Ca

s9generateiPSC

sinsin

gle

stepiPSC

s-M120601resistsHIV

1Im

mun

otherapy

ofSIDsHIV

1andother

immun

edise

ases

[808889]


Egg Blastocyst Embryo Embryonic stem cells

Diabetic treatment

Regeneration ofcardiac tissue

Drug screeningRegeneration of liver

Differentiation

COCO

Cone cells

ARMDtreatment

CardiomyocytesHepatocytes PPCsChondrocytes

Fibrin embedding

Regenerationof cartilage

RGC

Glaucoma treatmentDrug screening

ESCs in regenerative medicine

Pacemakercells

Restorationof heartrhythm

IVG

Infertilitytreatment

Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells

Figure 2 ESCs in regenerative medicine ESCs sourced from ICM of gastrula have tremendous promises in regenerative medicine Thesecells can differentiate into more than 200 types of cells representing three germ layers With defined culture conditions ESCs can betransformed into hepatocytes retinal ganglion cells chondrocytes pancreatic progenitor cells cone cells cardiomyocytes pacemaker cellseggs and sperms which can be used in regeneration of tissue and treatment of disease in tissue specific manner

and transdifferentiation processes [14] has been consideredas critical regulatory switch for lineage commitment of ESCsThe diverse lineage commitment potential represents ESCsas ideal model for regenerative therapeutics of disease andtissue anomalies This section of review on ESCs discussestransplantation and transdifferentiation of ESCs into retinalganglion hepatocytes cardiomyocytes pancreatic progeni-tors chondrocytes cones egg sperm and pacemaker cells(Figure 2 Table 1) Infection cancer treatment and accidentscan cause spinal cord injuries (SCIs) The transplantation ofhESCs to paraplegic or quadriplegic SCI patients improvesbody control balance sensation and limbal movements [15]where transplanted stem cells do homing to injury sites Bybirth humans have fixed numbers of cone cells degenerationof retinal pigment epithelium (RPE) of macula in centralretina causes age-relatedmacular degeneration (ARMD)Thegenomic incorporation of COCO gene (expressed duringembryogenesis) in the developing embryo leads lineagecommitment of ESCs into cone cells through suppression of

TGF120573 BMP and Wnt signalling pathways Transplantationof these cone cells to eye recovers individual from ARMDphenomenon where transplanted cone cells migrate andform sheet-like structure in host retina [16] However estab-lishment of missing neuronal connection of retinal ganglioncells (RGCs) cones andPRE is themost challenging aspect ofARMD therapeutics Recently Donald Z Jacks group at JohnHopkins University School of Medicine has generated RGCsfrom CRISPER-Cas9-m-Cherry reporter ESCs [17] DuringESCs transdifferentiation process CRIPER-Cas9 directs theknock-in of m-Cherry reporter into 31015840UTR of BRN3B genewhich is specifically expressed in RGCs and can be usedfor purification of generated RGCs from other cells [17]Furthermore incorporation of forskolin in transdifferenti-ation regime boosts generation of RGCs Coaxing of theseRGCs into biomaterial scaffolds directs axonal differenti-ation of RGCs Further modification in RGCs generationregime and composition of biomaterial scaffoldsmight enablerestoration of vision for ARMD and glaucoma patients [17]


TSPSCs in regenerative medicine


Ther

apeu

ticap

plic

atio

ns

Mesoangioblasts3D culture andtransplantation to mice tibialis

Tibialis anterior muscles

Treatment of myopathies

Fallopian tube organoid

RSPO1 mediumWnt3A medium3D Matrigel

Epithelial stem cells

Regeneration offallopian tube

Inner ear stem cellsLY411575

Auditory hair cells

Restoration ofacoustic function

SSCs

skinprostate intestine

Epithelium

Skin

Prostate

Intestine

Stem cells factors basedtransdifferentiation

Limbal stem cells

Transplantationin mice eye

Corneal occupancy

Restoration of vision

Pancreatic organoid

Pancreaticprogenitors

3Dculture

Insulin therapy

Intestinal progenitor

Intestinal tissue

Regeneration ofintestinal tissue

3D culture

Ther

apeu

ticap

plic

atio

ns

DPSCsNeuronalculture

Neurogenesis

Serotonin neurons

AdSCs


Treatment of ischemicheart disease

Infusion toMI heart

SKPs

VSMCs

WH and vasculatureregenerative therapy

containing 120573-cells

+Myofibroblasts+M120601bacteria

+Mesenchyma of

Figure 3 TSPSCs in regenerative medicine tissue specific stem and progenitor cells have potential to differentiate into other cells of thetissue Characteristically inner ear stem cells can be transformed into auditory hair cells skin progenitors into vascular smooth musclecells mesoangioblasts into tibialis anterior muscles and dental pulp stem cells into serotonin cells The 3D-culture of TSPSCs in complexbiomaterial gives rise to tissue organoids such as pancreatic organoid from pancreatic progenitor intestinal tissue organoids from intestinalprogenitor cells and fallopian tube organoids from fallopian tube epithelial cells Transplantation of TSPSCs regenerates targets tissue such asregeneration of tibialis muscles frommesoangioblasts cardiac tissue from AdSCs and corneal tissue from limbal stem cells Cell growth andtransformation factors secreted by TSPSCs can change cells fate to become other types of cell such that SSCs coculture with skin prostateand intestine mesenchyme transforms these cells fromMSCs into epithelial cells fate

Globally especially in India cardiovascular problems area more common cause of human death where biomedicaltherapeutics require immediate restoration of heart functionsfor the very survival of the patient Regeneration of cardiactissue can be achieved by transplantation of cardiomyocytesESCs-derived cardiovascular progenitors and bone marrowderivedmononuclear cells (BMDMNCs) however healing bycardiomyocytes and progenitor cells is superior to BMDM-NCs but mature cardiomyocytes have higher tissue healingpotential suppress heart arrhythmias couple electromag-netically into hearts functions and provide mechanical andelectrical repair without any associated tumorigenic effects

[18 19] Like CMdifferentiation ESCs derived liver stem cellscan be transformed into Cytp450-hepatocytes mediatingchemical modification and catabolism of toxic xenobioticdrugs [20] Even today availability and variability of func-tional hepatocytes are a major a challenge for testing drugtoxicity [20] Stimulation of ESCs and ex vivo VitK12 andlithocholic acid (a by-product of intestinal flora regulatingdrugmetabolism during infancy) activates pregnaneX recep-tor (PXR) CYP3A4 and CYP2C9 which leads to differ-entiation of ESCs into hepatocytes those are functionallysimilar to primary hepatocytes for their ability to producealbumin and apolipoprotein B100 [20] These hepatocytes


MSCsstromal cells in regenerative medicine

Muscle degenerativedisease treatment

MSCs

DPCS-LBL-GAG

DPCs-EPCsco transplantation

Hair reconstitution

Treatment ofacute liver failure

cirrhosis andregeneration

of bladder tissue


Regeneration ofbone tissue

Ligamentregeneration

Heart scar repairafter attack

Transplantationto liver

Healing oforthopedic injuries

Transplantation and trans-differentiation to orthopedic tissues

Muscle regeneration

coculture

leishmanial therapy CD73+CD90+CD105+CD34minusCD45minusCD11bminusCD14minusCD19minusCD79aminus

coating + FGF2

Educated M120601 for

AD-MSCs +M120601

Figure 4 MSCs in regenerative medicine mesenchymal stem cells are CD73+ CD90+ CD105+ CD34minus CD45minus CD11bminus CD14minus CD19minus andCD79aminus cells also known as stromal cellsThese bodily MSCs represented here do not account for MSCs of bone marrow and umbilical cordUpon transplantation and transdifferentiation these bodilyMSCs regenerate into cartilage bones andmuscles tissue Heart scar formed afterheart attack and liver cirrhosis can be treated from MSCs ECM coating provides the niche environment for MSCs to regenerate into hairfollicle stimulating hair growth

are excellent source for the endpoint screening of drugs foraccurate prediction of clinical outcomes [20] Generation ofhepatic cells from ESCs can be achieved in multiple waysas serum-free differentiation [21] chemical approaches [2022] and genetic transformation [23 24]These ESCs-derivedhepatocytes are long lasting source for treatment of liverinjuries and high throughput screening of drugs [20 23 24]Transplantation of the inert biomaterial encapsulated hESCs-derived pancreatic progenitors (CD24+ CD49+ andCD133+)differentiates into 120573-cells minimizing high fat diet inducedglycemic and obesity effects inmice [25] (Table 1) Addition ofantidiabetic drugs into transdifferentiation regime can boostESCs conservation into 120573-cells [25] which theoretically cancure T2DM permanently [25] ESCs can be differentiateddirectly into insulin secreting 120573-cells (marked with GLUT2INS1 GCK and PDX1) which can be achieved throughPDX1 mediated epigenetic reprogramming [26] Globallyosteoarthritis affects millions of people and occurs whencartilage at joints wears away causing stiffness of the jointsThe available therapeutics for arthritis relieve symptoms butdo not initiate reverse generation of cartilage For young

individuals and athletes replacement of joints is not feasiblelike old populations in that case transplantation of stem cellsrepresents an alternative for healing cartilage injuries [27]Chondrocytes the cartilage forming cells derived fromhESCembedded in fibrin gel effectively heal defective cartilagewithin 12 weeks when transplanted to focal cartilage defectsof knee joints in mice without any negative effect [27]Transplanted chondrocytes form cell aggregates positive forSOX9 and collagen II and defined chondrocytes are active formore than 12wks at transplantation site advocating clinicalsuitability of chondrocytes for treatment of cartilage lesions[27] The integrity of ESCs to integrate and differentiateinto electrophysiologically active cells provides a means fornatural regulation of heart rhythm as biological pacemakerCoaxing of ESCs into inert biomaterial as well as propagationin defined culture conditions leads to transdifferentiationof ESCs to become sinoatrial node (SAN) pacemaker cells(PCs) [28] Genomic incorporation TBox3 into ESCs exvivo leads to generation of PCs-like cells those expressactivated leukocyte cells adhesion molecules (ALCAM) andexhibit similarity to PCs for gene expression and immune


Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly

Amnion Umbilical cord bloodUmbilical vein

UCSCs in regenerative medicine

Ex vivo expansion of UCSCs

Intravenous delivery

Pancreatictransplantation

Treatment ofdiabetes

Treatment ofsystematic lupus

erythematosusMSCHSCs ProgenitorsUCSCs

Infusion of UCSCs

Treatment ofKrabbersquos disease

Ex vivo neurogenicorganoid culture

Application inneurodegenerative

disease

Treatment ofneuroblastoma

Treatment ofspinal myelitis

injection to pig knee

Regeneration oftendons

Injection of UCB-MSCs to rotor cuff

tendon tear-site

Regeneration of hyalinecartilage of knee

Treatment ofsevere congenital

neutropenia

Treatment ofHodgkinrsquoslymphoma

Intraperitonealtransplantation

Treatment of peritonealfibrosis occurred long

term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA

Figure 5 UCSCs in regenerative medicine umbilical cord the readily available source of stem cells has emerged as futuristic source forpersonalized stem cell therapy Transplantation of UCSCs to Krabbersquos disease patients regenerates myelin tissue and recovers neuroblastomapatients through restoring tissue homeostasis The UCSCs organoids are readily available tissue source for treatment of neurodegenerativedisease Peritoneal fibrosis caused by long term dialysis tendon tissue degeneration and defective hyaline cartilage can be regenerated byUCSCs Intravenous injection of UCSCs enables treatment of diabetes spinal myelitis systemic lupus erythematosus Hodgkinrsquos lymphomaand congenital neuropathies Cord blood stem cells banking avails long lasting source of stem cells for personalized therapy and regenerativemedicine

functions [28] Transplantation of PCs can restore pacemakerfunctions of the ailing heart [28] In summary ESCs canbe transdifferentiated into any kinds of cells representingthree germ layers of the body being most promising sourceof regenerative medicine for tissue regeneration and diseasetherapy (Table 1) Ethical concerns limit the applications ofESCs where set guidelines need to be followed in that caseTSPSCs MSCs UCSCs BMSCs and iPSCs can be exploredas alternatives

3 TSPSCs in Regenerative Medicine

TSPSCs maintain tissue homeostasis through continuouscell division but unlike ESCs TSPSCs retain stem cellsplasticity and differentiation in tissue specific manner givingrise to few types of cells (Table 1) The number of TSPSCs

population to total cells population is too low in thatcase their harvesting as well as in vitro manipulation isreally a tricky task [29] to explore them for therapeuticscale Human body has foundation from various types ofTSPSCs discussing the therapeutic application for all typesis not feasible This section of review discusses therapeuticapplication of pancreatic progenitor cells (PPCs) dental pulpstem cells (DPSCs) inner ear stem cells (IESCs) intestinalprogenitor cells (IPCs) limbal progenitor stem cells (LPSCs)epithelial progenitor stem cells (EPSCs) mesoangioblasts(MABs) spermatogonial stem cells (SSCs) the skin derivedprecursors (SKPs) and adipose derived stem cells (AdSCs)(Figure 3 Table 1) During embryogenesis PPCs give riseto insulin-producing 120573-cells The differentiation of PPCsto become 120573-cells is negatively regulated by insulin [30]PPCs require active FGF and Notch signalling growingmore rapidly in community than in single cell populations


BMSCs in regenerative medicine

BM-MSCCell perfusion anddecellularization

Diaphragm scaffold

BM-SSCBM-HSCBM-MSCBM-PSC

Application of BMSCs

Appl

icat

ions

Redmarrow

Separation oflymphoid andmyeloid cells

Allogenic transfusion

(i) Stromal stem cells (ii) Hematopoietic stem cells

(iii) Mesenchymal stem cells(iv) Progenitor stem cells

HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing

(CD14 and 90+) BMSCs

Craniofacial tissue

Periodonticbone formation

BMSCs

Intravenoustransplantationin diabetic mice Restoration of erectile

function in mice

BMSCs Transplantationto liver of liver

cirrhosis patients Regeneration of liverstissue and restoration

of liver functions

(CD4+) HSC and PSC

CD4+ cells

+3D culture +Epithelium+Spongy silk

+Transplantation +3D culture

+LA+HIV1 antisense

∙ Blood clotting and∙ Traumatic rain∙ HIV1 inhibition∙ Cancer treatment∙ CDD treatment

Figure 6 BMSCs in regenerative medicine bone marrow the soft sponge bone tissue that consisted of stromal hematopoietic andmesenchymal and progenitor stem cells is responsible for blood formation Even halo-HLA matched BMSCs can cure from disease andregenerate tissue BMSCs can regenerate craniofacial tissue brain tissue diaphragm tissue and liver tissue and restore erectile function andtransdifferentiation monocytes These multipotent stem cells can cure host from cancer and infection of HIV and HCV

advocates the functional importance of niche effect in self-renewal and transdifferentiation processes In 3D-scaffoldculture system mice embryo derived PPCs grow into holloworganoid spheres those finally differentiate into insulin-producing 120573-cell clusters [29] The DSPSCs responsible formaintenance of teeth health status can be sourced fromapicalpapilla deciduous teeth dental follicle and periodontalligaments have emerged as regenerative medicine candidateand might be explored for treatment of various kinds ofdisease including restoration neurogenic functions in teeth[31 32] Expansion ofDSPSCs in chemically defined neuronalculture medium transforms them into a mixed populationof cholinergic GABAergic and glutaminergic neurons thoseare known to respond towards acetylcholine GABA andglutamine stimulations in vivo These transformed neuronalcells express nestin glial fibrillary acidic protein (GFAP)120573III-tubulin and voltage gated L-type Ca2+ channels [32]However absence of Na+ and K+ channels does not sup-port spontaneous action potential generation necessary forresponse generation against environmental stimulus All

together these primordial neuronal stem cells have pos-sible therapeutic potential for treatment of neurodentalproblems [32] Sometimes brain tumor chemotherapy cancause neurodegeneration mediated cognitive impairment acondition known as chemobrain [33] The intrahippocampaltransplantation of human derived neuronal stem cells tocyclophosphamide behavioural decremented mice restorescognitive functions in a month time Here the transplantedstem cells differentiate into neuronal and astroglial lineagereduce neuroinflammation and restore microglial functions[33] Furthermore transplantation of stem cells followed bychemotherapy directs pyramidal and granule-cell neuronsof the gyrus and CA1 subfields of hippocampus which leadsto reduction in spine and dendritic cell density in thebrain These findings suggest that transplantation of stemcells to cranium restores cognitive functions of the chemo-brain [33] The hair cells of the auditory system producedduring development are not postmitotic loss of hair cellscannot be replaced by inner ear stem cells due to activestate of the Notch signalling [34] Stimulation of inner ear


iPSCs in regenerative medicine

iPSCs

Brain organoidLung organoid Cortical spheroids

Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient

iPSC factorsSkin cells

Heart valve cells

Skin cells

Immune cells Melanocytes

Serotonin neuronChimera Pacemaker cells

Treatmentof lungdefects

Regenerationof kidney

tissue

Healing ofbrain

defects

Chimerictransplantation

Brain cortexregeneration

Pacemakerimpairment

recovery

Psychodisordertherapeutics

Generationof placental

tissue

Regenerationof heart valve

Restorationof vision

Treatment of bloodand immune

disorders

Treatment ofskin defects

Appl

icat

ions

Appl

icat

ions

Regenerationof pancreas

+

120573-cells

Figure 7 iPSCs in regenerative medicine using the edge of iPSCs technology skin fibroblasts and other adult tissues derived terminallydifferentiated cells can be transformed into ESCs-like cells It is possible that adult cells can be transformed into cells of distinct lineagesbypassing the phase of pluripotency The tissue specific defined culture can transform skin cells to become trophoblast heart valve cellsphotoreceptor cells immune cells melanocytes and so forth ECM complexation with iPSCs enables generation of tissue organoids for lungkidney brain and other organs of the body Similar to ESCs iPSCs also can be transformed into cells representing three germ layers such aspacemaker cells and serotonin cells

progenitors with Υ-secretase inhibitor (LY411575) abrogatesNotch signalling through activation of transcription factoratonal homologue 1 (Atoh1) and directs transdifferentiationof progenitors into cochlear hair cells [34] Transplantationof in vitro generated hair cells restores acoustic functionsin mice which can be the potential regenerative medicinecandidates for the treatment of deafness [34] Generation ofthe hair cells also can be achieved through overexpression of120573-catenin and Atoh1 in Lrg5+ cells in vivo [35] Similar to earprogenitors intestine of the digestive tract also has its owntissue specific progenitor stem cells mediating regenerationof the intestinal tissue [34 36] Dysregulation of the commonstem cells signalling pathways NotchBMPTGF-120573Wnt inthe intestinal tissue leads to disease Information on thesesignalling pathways [37] is critically important in designingtherapeutics Coaxing of the intestinal tissue specific progeni-tors with immune cells (macrophages) connective tissue cells(myofibroblasts) and probiotic bacteria into 3D-scaffolds ofinert biomaterial crafting biological environment is suitablefor differentiation of progenitors to occupy the crypt-villistructures into these scaffolds [36] Omental implementationof these crypt-villi structures to dogs enhances intestinalmucosa through regeneration of goblet cells containing

intestinal tissue [36] These intestinal scaffolds are closeapproach for generation of implantable intestinal tissuedivested by infection trauma cancer necrotizing enterocol-itis (NEC) and so forth [36] In vitro culture conditionscause differentiation of intestinal stem cells to become othertypes of cells whereas incorporation of valproic acid andCHIR-99021 in culture conditions avoids differentiation ofintestinal stem cells enabling generation of indefinite poolof stem cells to be used for regenerative applications [38]The limbal stem cells of the basal limbal epithelium markedwith ABCB5 are essential for regeneration and maintenanceof corneal tissue [39] Functional status of ABCB5 is criticalfor survival and functional integrity of limbal stem cellsprotecting them from apoptotic cell death [39] Limbal stemcells deficiency leads to replacement of corneal epitheliumwith visually dead conjunctival tissue which can be con-tributed by burns inflammation and genetic factors [40]Transplanted human cornea stem cells to mice regrown intofully functional human cornea possibly supported by bloodeye barrier phenomena can be used for treatment of eyediseases where regeneration of corneal tissue is criticallyrequired for vision restoration [39] Muscle degenerativedisease like duchenne muscular dystrophy (DMD) can cause


Stem cells in wildlife conservation

Dead or livewild animals

Skin biopsies

Other internalorgan biopsies

iPSCs

Immaturegonadsbiopsies

In vitromaturation

In vivo maturation

Tissue specificstem cells

Cryopreservationtransdifferentiation

Cryopreservationin vitro fertilization


Resurrection of wildlife

Figure 8 Stem cells in wildlife conservation tissue biopsies obtained from dead and live wild animals can be either cryopreserved ortransdifferentiated to other types of cells through culture in defined culture medium or in vivo maturation Stem cells and adult tissuederived iPSCs have great potential of regenerative medicine and disease therapeutics Gonadal tissue procured from dead wild animals canbe matured ex vivo and in vivo for generation of sperm and egg which can be used for assistive reproductive technology oriented captivebreeding of wild animals or even for resurrection of wildlife

extensive thrashing ofmuscle tissue where tissue engineeringtechnology can be deployed for functional restoration oftissue through regeneration [41] Encapsulation of mouseor human derived MABs (engineered to express placentalderived growth factor (PDGF)) into polyethylene glycol(PEG) fibrinogen hydrogel and their transplantation beneaththe skin at ablated tibialis anterior form artificial muscleswhich are functionally similar to those of normal tibialisanterior muscles [41] The PDGF attracts various cell typesof vasculogenic and neurogenic potential to the site oftransplantation supporting transdifferentiation of mesoan-gioblasts to become muscle fibrils [41] The therapeuticapplication of MABs in skeletal muscle regeneration andother therapeutic outcomes has been reviewed by others [42]One of the most important tissue specific stem cells themale germline stem cells or spermatogonial stem cells (SSCs)produces spermatogenic lineage through mesenchymal andepithets cells [43] which itself creates niche effect on othercells In vivo transplantation of SSCs with prostate skinand uterine mesenchyme leads to differentiation of these

cells to become epithelia of the tissue of origin [43] Thesenewly formed tissues exhibit all physical and physiologicalcharacteristics of prostate and skin and the physical charac-teristics of prostate skin and uterus express tissue specificmarkers and suggest that factors secreted from SSCs leadto lineage conservation which defines the importance ofniche effect in regenerative medicine [43] According to anestimate more than 100 million people are suffering from thecondition of diabetic retinopathy a progressive dropout ofvascularisation in retina that leads to loss of vision [44] Theintravitreal injection of adipose derived stem cells (AdSCs)to the eye restores microvascular capillary bed in miceThe AdSCs from healthy donor produce higher amounts ofvasoprotective factors compared to glycemic mice enablingsuperior vascularisation [44] However use of AdSCs fordisease therapeutics needs further standardization for cellcounts in dose of transplant and monitoring of therapeuticoutcomes at population scale [44] Apart from AdSCs otherkinds of stem cells also have therapeutic potential in regen-erative medicine for treatment of eye defects which has been


reviewed by others [45] Fallopian tubes connecting ovariesto uterus are the sites where fertilization of the egg takesplace Infection in fallopian tubes can lead to inflammationtissue scarring and closure of the fallopian tube which oftenleads to infertility and ectopic pregnancies Fallopian is alsothe site where onset of ovarian cancer takes placeThe studieson origin and etiology of ovarian cancer are restricted dueto lack of technical advancement for culture of epithelialcells The in vitro 3D organoid culture of clinically obtainedfallopian tube epithelial cells retains their tissue specificitykeeps cells alive which differentiate into typical ciliated andsecretory cells of fallopian tube and advocates that ectopicexamination of fallopian tube in organoid culture settingsmight be the ideal approach for screening of cancer [46]Thesustained growth and differentiation of fallopian TSPSCs intofallopian tube organoid depend both on the active state ofthe Wnt and on paracrine Notch signalling [46] Similar tofallopian tube stem cells subcutaneous visceral tissue specificcardiac adipose (CA) derived stem cells (AdSCs) have thepotential of differentiation into cardiovascular tissue [47]Systemic infusion of CA-AdSCs into ischemic myocardiumof mice regenerates heart tissue and improves cardiac func-tion through differentiation to endothelial cells vascularsmooth cells and cardiomyocytes and vascular smooth cellsThe differentiation and heart regeneration potential of CA-AdSCs are higher than AdSCs [48] representing CA-AdSCsas potent regenerative medicine candidates for myocardialischemic therapy [47] The skin derived precursors (SKPs)the progenitors of dermal papillahairhair sheath give riseto multiple tissues of mesodermal andor ectodermal originsuch as neurons Schwann cells adipocytes chondrocytesand vascular smooth muscle cells (VSMCs) VSMCs mediatewound healing and angiogenesis process can be derivedfrom human foreskin progenitor SKPs suggesting that SKPsderived VSMCs are potential regenerative medicine candi-dates for wound healing and vasculature injuries treatments[49] In summary TSPSCs are potentiated with tissue regen-eration where advancement in organoid culture (Figure 3Table 1) technologies defines the importance of niche effectin tissue regeneration and therapeutic outcomes of ex vivoexpanded stem cells

4 MSCsStromal Cells inRegenerative Medicine

MSCs the multilineage stem cells differentiate only totissue of mesodermal origin which includes tendons bonecartilage ligaments muscles and neurons [50] MSCs arethe cells which express combination of markers CD73+CD90+ CD105+ CD11bminus CD14minus CD19minus CD34minus CD45minusCD79aminus and HLA-DR reviewed elsewhere [50] The appli-cation of MSCs in regenerative medicine can be generalizedfrom ongoing clinical trials phasing through different stateof completions reviewed elsewhere [90] This section ofreview outlines the most recent representative applications ofMSCs (Figure 4 Table 1) The anatomical and physiologicalcharacteristics of both donor and receiver have equal impacton therapeutic outcomes The bone marrow derived MSCs

(BMDMSCs) from baboon are morphologically and pheno-typically similar to those of bladder stem cells and can be usedin regeneration of bladder tissue The BMDMSCs (CD105+CD73+ CD34minus and CD45minus) expressing GFP reportercoaxed with small intestinal submucosa (SIS) scaffolds aug-ment healing of degenerated bladder tissue within 10wks ofthe transplantation [51]The combinatorial CD characterizedMACs are functionally active at transplantation site whichsuggests that CD characterization of donorMSCs yields supe-rior regenerative outcomes [51] MSCs also have potentialto regenerate liver tissue and treat liver cirrhosis reviewedelsewhere [91] The regenerative medicinal application ofMSCs utilizes cells in two formats as direct transplantationor first transdifferentiation and then transplantation exvivo transdifferentiation of MSCs deploys retroviral deliverysystem that can cause oncogenic effect on cells NonviralNanoScript technology comprising utility of transcriptionfactors (TFs) functionalized gold nanoparticles can targetspecific regulatory site in the genome effectively and directdifferentiation of MSCs into another cell fate dependingon regime of TFs For example myogenic regulatory factorcontaining NanoScript-MRF differentiates the adipose tissuederived MSCs into muscle cells [92] The multipotency char-acteristics representMSCs as promising candidate for obtain-ing stable tissue constructs through coaxed 3D organoidculture however heterogeneous distribution of MSCs slowsdown cell proliferation rendering therapeutic applicationsof MSCs Adopting two-step culture system for MSCs canyield homogeneous distribution of MSCs in biomaterialscaffolds For example fetal-MSCs coaxed in biomaterialwhen cultured first in rotating bioreactor followed with staticculture lead to homogeneous distribution of MSCs in ECMcomponents [7] Occurrence of dental carries periodontaldisease and tooth injury can impact individualrsquos healthwhere bioengineering of teeth can be the alternative optionCoaxing of epithelial-MSCs with dental stem cells into syn-thetic polymer gives rise tomature teeth unit which consistedof mature teeth and oral tissue offering multiple regenerativetherapeutics reviewed elsewhere [52] Like the tooth decayboth human and animals are prone to orthopedic injuriesaffecting bones joint tendonmuscles cartilage and so forthAlthoughnatural healing potential of bone is sufficient to healthe common injuries severe trauma and tumor-recessioncan abrogate germinal potential of bone-forming stem cellsIn vitro chondrogenic osteogenic and adipogenic potentialof MSCs advocates therapeutic applications of MSCs inorthopedic injuries [53] Seeding of MSCs coaxed intobiomaterial scaffolds at defective bone tissue regeneratesdefective bone tissues within fourwks of transplantation bythe end of 32wks newly formed tissues integrate into old bone[54] Osteoblasts the bone-forming cells have lesser actincytoskeleton compared to adipocytes and MSCs Treatmentof MSCs with cytochalasin-D causes rapid transportationof G-actin leading to osteogenic transformation of MSCsFurthermore injection of cytochalasin-D to mice tibia alsopromotes bone formation within a wk time frame [55]The bone formation processes in mice dog and humanare fundamentally similar so outcomes of research on miceand dogs can be directional for regenerative application to


human Injection of MSCs to femur head of Legg-Calve-Perthes suffering dog heals the bone very fast and reduces theinjury associated pain [55] Degeneration of skeletal muscleandmuscle cramps are very common to sledge dogs animalsand individuals involved in adventurous athletics activitiesDirect injection of adipose tissue derived MSCs to tear-siteof semitendinosus muscle in dogs heals injuries much fasterthan traditional therapies [56] Damage effect treatmentfor heart muscle regeneration is much more complex thanregeneration of skeletal muscles which needs high gradefine-tuned coordination of neurons withmuscles Coaxing ofMSCs into alginate gel increases cell retention time that leadsto releasing of tissue repairing factors in controlled man-ner Transplantation of alginate encapsulated cells to miceheart reduces scar size and increases vascularisation whichleads to restoration of heart functions Furthermore trans-planted MSCs face host inhospitable inflammatory immuneresponses and other mechanical forces at transplantationsite where encapsulation of cells keeps them away from allsorts of mechanical forces and enables sensing of host tissuemicroenvironment and respond accordingly [57] Ageingdisease and medicine consumption can cause hair lossknown as alopecia Although alopecia has no life threateningeffects emotional catchments can lead to psychological dis-turbance The available treatments for alopecia include hairtransplantation and use of drugs where drugs are expensiveto afford and generation of new hair follicle is challengingDermal papillary cells (DPCs) the specialized MSCs local-ized in hair follicle are responsible for morphogenesis ofhair follicle and hair cycling The layer-by-layer coating ofDPCs called GAG coating consists of coating of geletinas outer layer middle layer of fibroblast growth factor 2(FGF2) loaded alginate and innermost layer of geletin GAGcoating creates tissue microenvironment for DPCs that cansustain immunological andmechanical obstacles supportinggeneration of hair follicle Transplantation of GAG-coatedDPCs leads to abundant hair growth and maturation ofhair follicle where GAG coating serves as ECM enhanc-ing intrinsic therapeutic potential of DPCs [58] Duringinfection the inflammatory cytokines secreted from hostimmune cells attractMSCs to the site of inflammation whichmodulates inflammatory responses representing MSCs askey candidate of regenerative medicine for infectious diseasetherapeutics Coculture of macrophages (M120601) and adiposederived MSCs from Leishmania major (LM) susceptible andresistant mice demonstrates that AD-MSCs educate M120601against LM infection differentially inducing M1 and M2phenotype that represents AD-MSC as therapeutic agentfor leishmanial therapy [93] In summary the multilineagedifferentiation potential of MSCs as well as adoption of next-generation organoid culture system avails MSCs as idealregenerative medicine candidate

5 UCSCs in Regenerative Medicine

Umbilical cord generally thrown at the time of child birthis the best known source for stem cells procured in nonin-vasive manner having lesser ethical constraints than ESCs

Umbilical cord is rich source of hematopoietic stem cells(HSCs) and MSCs which possess enormous regenerationpotential [94] (Figure 5 Table 1) The HSCs of cord bloodare responsible for constant renewal of all types of blood cellsand protective immune cells The proliferation of HSCs isregulated by Musashi-2 protein mediated attenuation of Arylhydrocarbon receptor (AHR) signalling in stem cells [95]UCSCs can be cryopreserved at stem cells banks (Figure 5Table 1) in operation by both private and public sectororganization Public stem cells banks operate on donationformats and perform rigorous screening for HLA typingand donated UCSCs remain available to anyone in needwhereas private stem cell banks operation is more person-alized availing cells according to donor consent Stem cellbanking is not so common even in developed countriesSurvey studies find that educated women are more eagerto donate UCSCs but willingness for donation decreaseswith subsequent deliveries due to associated cost and safetyconcerns for preservation [96] FDA has approved five HSCsfor treatment of blood and other immunological complica-tions [97] The amniotic fluid drawn during pregnancy forstandard diagnostic purposes is generally discarded withoutconsidering its vasculogenic potential UCSCs are the bestalternatives for those patients who lack donors with fullymatched HLA typing for peripheral blood and PBMCs andbone marrow [98] One major issue with UCSCs is numberof cells in transplant fewer cells in transplant require moretime for engraftment to mature and there are also risks ofinfection and mortality in that case ex vivo propagation ofUCSCs can meet the demand of desired outcomes Thereare diverse protocols available for ex vivo expansion ofUCSCs reviewed elsewhere [99] Amniotic fluid stem cells(AFSCs) coaxed to fibrin (required for blood clotting ECMinteractions wound healing and angiogenesis) hydrogel andPEG supplemented with vascular endothelial growth factor(VEGF) give rise to vascularised tissue when grafted tomicesuggesting that organoid cultures of UCSCs have promisefor generation of biocompatible tissue patches for treatinginfants born with congenital heart defects [59] Retroviralintegration of OCT4 KLF4 cMYC and SOX2 transformsAFSCs into pluripotency stem cells known as AFiPSCswhich can be directed to differentiate into extraembryonictrophoblast by BMP2 and BMP4 stimulation which can beused for regeneration of placental tissues [60] Whartonrsquosjelly (WJ) the gelatinous substance inside umbilical cordis rich in mucopolysaccharides fibroblast macrophagesand stem cells The stem cells from UCB and WJ can betransdifferentiated into 120573-cells Homogeneous nature of WJ-SCs enables better differentiation into 120573-cells transplanta-tion of these cells to streptozotocin induced diabetic miceefficiently brings glucose level to normal [7] Easy accessand expansion potential and plasticity to differentiate intomultiple cell lineages represent WJ as an ideal candidatefor regenerative medicine but cells viability changes withpassages with maximum viable population at 5th-6th pas-sages So it is suggested to perform controlled expansionof WJ-MSCS for desired regenerative outcomes [9] Studysuggests that CD34+ expression leads to the best regenerativeoutcomes with less chance of host-versus-graft rejection In


vitro expansion of UCSCs in presence of StemRegenin-1 (SR-1) conditionally expands CD34+ cells [61] In type I diabeticmellitus (T1DM) T-cell mediated autoimmune destructionof pancreatic 120573-cells occurs which has been considered astough to treat Transplantation of WJ-SCs to recent onset-T1DM patients restores pancreatic function suggesting thatWJ-MSCs are effective in regeneration of pancreatic tissueanomalies [62] WJ-MSCs also have therapeutic importancefor treatment of T2DM A non-placebo controlled phase IIIclinical trial demonstrates that intravenous and intrapancre-atic endovascular injection of WJ-MSCs to T2DM patientscontrols fasting glucose and glycated haemoglobin throughimprovement of 120573-cells functions evidenced by enhanced c-peptides and reduced inflammatory cytokines (IL-1120573 and IL-6) and T-cells counts [63] Like diabetes systematic lupuserythematosus (SLE) also can be treated with WJ-MSCstransplantation During progression of SLE host immunesystem targets its own tissue leading to degeneration ofrenal cardiovascular neuronal and musculoskeletal tissuesA non-placebo controlled follow-up study on 40 SLE patientsdemonstrates that intravenous infusion ofWJ-MSC improvesrenal functions and decreases systematic lupus erythemato-sus disease activity index (SLEDAI) and British Isles LupusAssessment Group (BILAG) and repeated infusion of WJ-MSCs protects the patient from relapse of the disease [64]Sometimes host inflammatory immune responses can bedetrimental for HSCs transplantation and blood transfu-sion procedures Infusion of WJ-MSC to patients whohad allogenic HSCs transplantation reduces haemorrhageinflammation (HI) of bladder suggesting that WJ-MSCs arepotential stem cells adjuvant in HSCs transplantation andblood transfusion based therapies [100] Apart from WJumbilical cord perivascular space and cord vein are alsorich source for obtaining MSCs The perivascular MSCsof umbilical cord are more primitive than WJ-MSCs andother MSCs from cord suggest that perivascular MSCsmight be used as alternatives for WJ-MSCs for regenerativetherapeutics outcome [101] Based on origin MSCs exhibitdifferential in vitro and in vivo properties and advocatefunctional characterization of MSCs prior to regenerativeapplications Emerging evidence suggests that UCSCs canheal brain injuries caused by neurodegenerative diseaseslike Alzheimerrsquos Krabbersquos disease and so forth Krabbersquosdisease the infantile lysosomal storage disease occurs dueto deficiency of myelin synthesizing enzyme (MSE) affectingbrain development and cognitive functions Progression ofneurodegeneration finally leads to death of babies agedtwo Investigation shows that healing of peripheral nervoussystem (PNS) and central nervous system (CNS) tissues withKrabbersquos disease can be achieved by allogenic UCSCs UCSCstransplantation to asymptomatic infants with subsequentmonitoring for 4ndash6 years reveals that UCSCs recover babiesfrom MSE deficiency improving myelination and cognitivefunctions compared to those of symptomatic babies Thesurvival rate of transplanted UCSCs in asymptomatic andsymptomatic infants was 100 and 43 respectively sug-gesting that early diagnosis and timely treatment are criticalfor UCSCs acceptance for desired therapeutic outcomesUCSCs are more primitive than BMSCs so perfect HLA

typing is not critically required representing UCSCs as anexcellent source for treatment of all the diseases involvinglysosomal defects like Krabbersquos disease hurler syndromeadrenoleukodystrophy (ALD) metachromatic leukodystro-phy (MLD) Tay-Sachs disease (TSD) and Sandhoff disease[65] Brain injuries often lead to cavities formation whichcan be treated from neuronal parenchyma generated ex vivofrom UCSCs Coaxing of UCSCs into human originatedbiodegradable matrix scaffold and in vitro expansion ofcells in defined culture conditions lead to formation ofneuronal organoids within threewksrsquo time frame Theseorganoids structurally resemble brain tissue and consistedof neuroblasts (GFAP+ Nestin+ and Ki67+) and immaturestem cells (OCT4+ and SOX2+) The neuroblasts of theseorganoids further can be differentiated into mature neurons(MAP2+ and TUJ1+) [66] Administration of high doseof drugs in divesting neuroblastoma therapeutics requiresimmediate restoration of hematopoiesis Although BMSCshad been promising in restoration of hematopoiesis UCSCsare sparely used in clinical settings A case study demonstratesthat neuroblastoma patients who received autologous UCSCssurvive without any associated side effects [12] Duringradiation therapy of neoplasm spinal cordmyelitis can occuralthough occurrence of myelitis is a rare event and usuallysuch neurodegenerative complication of spinal cord occurs6ndash24 years after exposure to radiations Transplantation ofallogenic UC-MSCs in laryngeal patients undergoing radi-ation therapy restores myelination [102] For treatment ofneurodegenerative disease like Alzheimerrsquos disease (AD)amyotrophic lateral sclerosis (ALS) traumatic brain injuries(TBI) Parkinsonrsquos SCI stroke and so forth distributionof transplanted UCSCs is critical for therapeutic outcomesIn mice and rat injection of UCSCs and subsequent MRIscanning show that transplanted UCSCs migrate to CNS andmultiple peripheral organs [67] For immunomodulation oftumor cells disease recovery transplantation of allogenicDCsis required The CD11c+DCs derived from UCB are mor-phologically and phenotypically similar to those of peripheralblood derived CTLs-DCs suggesting that UCB-DCs can beused for personalized medicine of cancer patient in need forDCs transplantation [103] Coculture of UCSCs with radia-tion exposed human lung fibroblast stops their transdifferen-tiation which suggests that factors secreted fromUCSCsmayrestore niche identity of fibroblast if they are transplantedto lung after radiation therapy [104] Tearing of shouldercuff tendon can cause severe pain and functional disabilitywhereas ultrasound guided transplantation of UCB-MSCsin rabbit regenerates subscapularis tendon in fourwksrsquo timeframe suggesting that UCB-MSCs are effective enough totreat tendons injuries when injected to focal points of tear-site[68] Furthermore transplantation of UCB-MSCs to chon-dral cartilage injuries site in pig knee along with HA hydrogelcomposite regenerates hyaline cartilage [69] suggesting thatUCB-MSCs are effective regenerative medicine candidatefor treating cartilage and ligament injuries Physiologicallycirculatory systems of brain placenta and lungs are similarInfusion of UCB-MSCs to preeclampsia (PE) induced hyper-tension mice reduces the endotoxic effect suggesting thatUC-MSCs are potential source for treatment of endotoxin


induced hypertension during pregnancy drug abuse andother kinds of inflammatory shocks [105] Transplantationof UCSCs to severe congenital neutropenia (SCN) patientsrestores neutrophils count from donor cells without anyside effect representing UCSCs as potential alternative forSCN therapy when HLA matched bone marrow donorsare not accessible [106] In clinical settings the success ofmyocardial infarction (MI) treatment depends on ageingsystemic inflammation in host and processing of cells forinfusion Infusion of human hyaluronan hydrogel coaxedUCSCs in pigs induces angiogenesis decreases scar areaimproves cardiac function at preclinical level and suggeststhat the same strategy might be effective for human [107] Instem cells therapeutics UCSCs transplantation can be eitherautologous or allogenic Sometimes the autologous UCSCstransplants cannot combat over tumor relapse observed inHodgkinrsquos lymphoma (HL) which might require seconddose transplantation of allogenic stem cells but efficacy andtolerance of stem cells transplant need to be addressedwhere tumor replace occurs A case study demonstrates thatsecond dose allogenic transplants of UCSCs effective for HLpatients who had heavy dose in prior transplant increase thelong term survival chances by 30 [10] Patients undergoinglong term peritoneal renal dialysis are prone to peritonealfibrosis and can change peritoneal structure and failure ofultrafiltration processes The intraperitoneal (IP) injection ofWJ-MSCs prevents methylglyoxal induced programmed celldeath and peritoneal wall thickening and fibrosis suggestingthat WJ-MSCs are effective in therapeutics of encapsulatingperitoneal fibrosis [70] In summary UCB-HSCs WJ-MSCsperivascular MSCs and UCB-MSCs have tissue regenerationpotential

6 BMSCs in Regenerative Medicine

Bone marrow found in soft spongy bones is responsible forformation of all peripheral blood and comprises hematopoi-etic stem cells (producing blood cells) and stromal cells(producing fat cartilage and bones) [108] (Figure 6 Table 1)Visually bone marrow has two types red marrow (myeloidtissue producing RBC platelets and most of WBC) andyellow marrow (producing fat cells and some WBC) [108]Imbalance in marrow composition can culminate to thediseased condition Since 1980 bone marrow transplantationis widely accepted for cancer therapeutics [109] In order toavoid graft rejection HLA typing of donors is a must butcompletely matched donors are limited to family memberswhich hampers allogenic transplantation applications Sincematching of all HLA antigens is not critically required in thatcase defining the critical antigens for haploidentical allogenicdonor for patients who cannot find fully matched donormight relieve from donor constraints Two-step administra-tion of lymphoid and myeloid BMSCs from haploidenticaldonor to the patients of aplastic anaemia and haematologicalmalignancies reconstructs host immune system and theoutcomes are almost similar to fully matched transplantswhich recommends that profiling of critically importantHLA

is sufficient for successful outcomes of BMSCs transplan-tation Haploidentical HLA matching protocol is the majorprocess for minorities and others who do not have accessto matched donor [71] Furthermore antigen profiling isnot the sole concern for BMSCs based therapeutics Forexample restriction of HIV1 (human immune deficiencyvirus) infection is not feasible through BMSCs transplan-tation because HIV1 infection is mediated through CD4+receptors chemokine CXC motif receptor 4 (CXCR4) andchemokine receptor 5 (CCR5) for infecting and propagatinginto T helper (Th) monocytes macrophages and dendriticcells (DCs) Genetic variation in CCR2 and CCR5 receptorsis also a contributory factor mediating protection againstinfection has been reviewed elsewhere [110] Engineering ofhematopoietic stem and progenitor cells (HSPCs) derivedCD4+ cells to express HIV1 antagonistic RNA specificallydesigned for targeting HIV1 genome can restrict HIV1infection through immune elimination of latently infectedCD4+ cells A single dose infusion of genetically modified(GM) HIV1 resistant HSPCs can be the alternative of HIV1retroviral therapy In the present scenario stem cells sourcepatient selection transplantation-conditioning regimen andpostinfusion follow-up studies are the major factors whichcan limit application of HIV1 resistant GM-HSPCs (CD4+)cells application in AIDS therapy [72 73] Platelets essentialfor blood clotting are formed from megakaryocytes insidethe bone marrow [74] Due to infection trauma and cancerthere are chances of bone marrow failure To an extentspongy bone marrow microenvironment responsible forlineage commitment can be reconstructed ex vivo [75] Theex vivo constructed 3D-scaffolds consisted of microtubuleand silk sponge flooded with chemically defined organculture medium which mimics bone marrow environmentThe coculture of megakaryocytes and embryonic stem cells(ESCs) in this microenvironment leads to generation offunctional platelets from megakaryocytes [75] The ex vivo3D-scaffolds of bone microenvironment can stride the pathfor generation of platelets in therapeutic quantities for regen-erativemedication of burns [75] and blood clotting associateddefects Accidents traumatic injuries and brain stroke candeplete neuronal stem cells (NSCs) responsible for genera-tion of neurons astrocytes and oligodendrocytes Brain doesnot repopulate NSCs and heal traumatic injuries itself andtransplantation of BMSCs also can heal neurodegenerationalone Lipoic acid (LA) a known pharmacological antioxi-dant compound used in treatment of diabetic and multiplesclerosis neuropathy when combined with BMSCs inducesneovascularisation at focal cerebral injuries within 8wksof transplantation Vascularisation further attracts microgliaand induces their colonization into scaffold which leadsto differentiation of BMSCs to become brain tissue within16wks of transplantation In this approach healing of tissuedirectly depends on number of BMSCs in transplantationdose [76] Dental caries and periodontal disease are commoncraniofacial disease often requiring jaw bone reconstructionafter removal of the teeth Traditional therapy focuses onfunctional and structural restoration of oral tissue boneand teeth rather than biological restoration but BMSCsbased therapies promise for regeneration of craniofacial bone


defects enabling replacement of missing teeth in restoredbones with dental implants Bone marrow derived CD14+and CD90+ stem and progenitor cells termed as tissuerepair cells (TRC) accelerate alveolar bone regeneration andreconstruction of jaw bone when transplanted in damagedcraniofacial tissue earlier to oral implants Hence TRCtherapy reduces the need of secondary bone grafts bestsuited for severe defects in oral bone skin and gumresulting from trauma disease or birth defects [77] OverallHSCs have great value in regenerative medicine where stemcells transplantation strategies explore importance of nichein tissue regeneration Prior to transplantation of BMSCsclearance of original niche from target tissue is necessaryfor generation of organoid and organs without host-versus-graft rejection events Some genetic defects can lead todisorganization of niche leading to developmental errorsComplementation with human blastocyst derived primarycells can restore niche function of pancreas in pigs andrats which defines the concept for generation of clinicalgrade human pancreas in mice and pigs [111] Similar toother organs diaphragm also has its own niche Congenitaldefects in diaphragm can affect diaphragm functions Inthe present scenario functional restoration of congenitaldiaphragm defects by surgical repair has risk of reoccurrenceof defects or incomplete restoration [8] Decellularization ofdonor derived diaphragm offers a way for reconstruction ofnew and functionally compatible diaphragm through nichemodulation Tissue engineering technology based decel-lularization of diaphragm and simultaneous perfusion ofbonemarrowmesenchymal stem cells (BM-MSCs) facilitatesregeneration of functional scaffolds of diaphragm tissues [8]In vivo replacement of hemidiaphragm in rats with reseededscaffolds possesses similar myography and spirometry as ithas in vivo in donor rats These scaffolds retaining naturalarchitecture are devoid of immune cells retaining intactextracellular matrix that supports adhesion proliferationand differentiation of seeded cells [8] These findings suggestthat cadaver obtained diaphragm seeded with BM-MSCscan be used for curing patients in need for restoration ofdiaphragm functions (Figure 6 Table 1) However BMSCs areheterogeneous population which might result in differentialoutcomes in clinical settings however clonal expansion ofBMSCs yields homogenous cells population for therapeuticapplication [8] One study also finds that intracavernousdelivery of single clone BMSCs can restore erectile func-tion in diabetic mice [112] and the same strategy mightbe explored for adult human individuals The infectionof hepatitis C virus (HCV) can cause liver cirrhosis anddegeneration of hepatic tissue The intraparenchymal trans-plantation of bone marrow mononuclear cells (BMMNCs)into liver tissue decreases aspartate aminotransferase (AST)alanine transaminase (ALT) bilirubin CD34 and 120572-SMAsuggesting that transplantedBMSCs restore hepatic functionsthrough regeneration of hepatic tissues [113] In order tomeetthe growing demand for stem cells transplantation therapydonor encouragement is always required [8] The stem cellsdonation procedure is very simple with consent donorgets an injection of granulocyte-colony stimulating factor(G-CSF) that increases BMSCs population Bone marrow

collection is done from hip bone using syringe in 4-5 hrsrequiring local anaesthesia andwithin a wk time frame donorgets recovered donation associated weakness

7 iPSCs in Regenerative Medicine

The field of iPSCs technology and research is new to allother stem cells research emerging in 2006 when for thefirst time Takahashi and Yamanaka generated ESCs-likecells through genetic incorporation of four factors Sox2Oct34 Klf4 and c-Myc into skin fibroblast [3] Due toextensive nuclear reprogramming generated iPSCs are indis-tinguishable from ESCs for their transcriptome profilingepigenetic markings and functional competence [3] but useof retrovirus in transdifferentiation approach has questionediPSCs technology Technological advancement has enabledgeneration of iPSCs from various kinds of adult cells phasingthrough ESCs or direct transdifferentiation This section ofreview outlinesmost recent advancement in iPSC technologyand regenerative applications (Figure 7 Table 1) Using thenew edge of iPSCs technology terminally differentiated skincells directly can be transformed into kidney organoids [114]which are functionally and structurally similar to those ofkidney tissue in vivo Up to certain extent kidneys healthemselves however natural regeneration potential cannotmeet healing for severe injuries During kidneys healingprocess a progenitor stem cell needs to become 20 typesof cells required for waste excretion pH regulation andrestoration of water and electrolytic ions The procedure forgeneration of kidney organoids ex vivo containing functionalnephrons has been identified for human These ex vivokidney organoids are similar to fetal first-trimester kidneysfor their structure and physiology Such kidney organoidscan serve as model for nephrotoxicity screening of drugsdisease modelling and organ transplantation However gen-eration of fully functional kidneys is a far seen event withtodayrsquos scientific technologies [114] Loss of neurons inage-related macular degeneration (ARMD) is the commoncause of blindness At preclinical level transplantation ofiPSCs derived neuronal progenitor cells (NPCs) in rat limitsprogression of disease through generation of 5-6 layers ofphotoreceptor nuclei restoring visual acuity [78]The variousapproaches of iPSCs mediated retinal regeneration includingARMD have been reviewed elsewhere [79] Placenta thecordial connection between mother and developing fetusgets degenerated in certain pathophysiological conditionsNuclear programming of OCT4 knock-out (KO) and wildtype (WT) mice fibroblast through transient expressionof GATA3 EOMES TFAP2C and +minus cMYC generatestransgene independent trophoblast stem-like cells (iTSCs)which are highly similar to blastocyst derived TSCs for DNAmethylation H3K7ac nucleosome deposition of H2AX andother epigenetic markings Chimeric differentiation of iTSCsspecifically gives rise to haemorrhagic lineages and placentaltissue bypassing pluripotency phase opening an avenuefor generation of fully functional placenta for human [115]Neurodegenerative disease like Alzheimerrsquos and obstinateepilepsies can degenerate cerebrum controlling excitatory


and inhibitory signals of the brain The inhibitory tones incerebral cortex and hippocampus are accounted by 120574-aminobutyric acid secreting (GABAergic) interneurons (INs) Lossof these neurons often leads to progressive neurodegen-eration Genomic integration of Ascl1 Dlx5 Foxg1 andLhx6 to mice and human fibroblast transforms these adultcells into GABAergic-INs (iGABA-INs) These cells havemolecular signature of telencephalic INs release GABAand show inhibition to host granule neuronal activity [81]Transplantation of these INs in developing embryo curesfrom genetic and acquired seizures where transplanted cellsdisperse andmature into functional neuronal circuits as localINs [82] Dorsomorphin and SB-431542 mediated inhibitionof TGF-120573 and BMP signalling direct transformation ofhuman iPSCs into cortical spheroidsThese cortical spheroidsconsisted of both peripheral and cortical neurons sur-rounded by astrocytes displaying transcription profiling andelectrophysiology similarity with developing fetal brain andmature neurons respectively [83] The underlying complexbiology and lack of clear etiology and genetic reprogram-ming and difficulty in recapitulation of brain developmenthave barred understanding of pathophysiology of autismspectrum disorder (ASD) and schizophrenia 3D organoidcultures of ASD patient derived iPSC generate miniaturebrain organoid resembling fetal brain few months aftergestation The idiopathic conditions of these organoids aresimilar with brain of ASD patients both possess higherinhibitory GABAergic neurons with imbalanced neuronalconnection Furthermore these organoids express forkheadBox G1 (FOXG1) much higher than normal brain tissuewhich explains that FOXG1 might be the leading cause ofASD [84] Degeneration of other organs and tissues alsohas been reported like degeneration of lungs which mightoccur due to tuberculosis infection fibrosis and cancer Theunderlying etiology for lung degeneration can be explainedthrough organoid culture Coaxing of iPSC into inert bio-material and defined culture leads to formation of lungorganoids that consisted of epithelial and mesenchymal cellswhich can survive in culture for months These organoidsare miniature lung resemble tissues of large airways andalveoli and can be used for lung developmental studiesand screening of antituberculosis and anticancer drugs [87]The conventional multistep reprogramming for iPSCs con-sumes months of time while CRISPER-Cas9 system basedepisomal reprogramming system that combines two stepstogether enables generation of ESCs-like cells in less thantwowks reducing the chances of culture associated geneticabrasions and unwanted epigenetic [80] This approach canyield single step ESCs-like cells in more personalized wayfrom adults with retinal degradation and infants with severeimmunodeficiency involving correction for geneticmutationof OCT4 and DNMT3B [80] The iPSCs expressing anti-CCR5-RNA which can be differentiated into HIV1 resistantmacrophages have applications in AIDS therapeutics [88]The diversified immunotherapeutic application of iPSCs hasbeen reviewed elsewhere [89] The 120572-1 antitrypsin deficiency(A1AD) encoded by serpin peptidase inhibitor clade Amember 1 (SERPINA1) protein synthesized in liver pro-tects lungs from neutrophils elastase the enzyme causing

disruption of lungs connective tissue A1AD deficiency iscommon cause of both lung and liver disease like chronicobstructive pulmonary disease (COPD) and liver cirrhosisPatient specific iPSCs from lung and liver cells might explainpathophysiology of A1AD deficiency COPD patient derivediPSCs show sensitivity to toxic drugs which explains thatactual patient might be sensitive in similar fashion It isknown that A1AD deficiency is caused by single base pairmutation and correction of thismutation fixes theA1ADdefi-ciency in hepatic-iPSCs [85] The high order brain functionslike emotions anxiety sleep depression appetite breathingheartbeats and so forth are regulated by serotonin neuronsGeneration of serotonin neurons occurs prior to birth whichare postmitotic in their nature Any sort of developmentaldefect and degeneration of serotonin neurons might leadto neuronal disorders like bipolar disorder depression andschizophrenia-like psychiatric conditions Manipulation ofWnt signalling in human iPSCs in defined culture conditionsleads to an in vitro differentiation of iPSCs to serotonin-like neurons These iPSCs-neurons primarily localize torhombomere 2-3 segment of rostral raphe nucleus exhibitelectrophysiological properties similar to serotonin neuronsexpress hydroxylase 2 the developmental marker and releaseserotonin in dose and time dependent manner Transplanta-tion of these neurons might cure from schizophrenia bipolardisorder and other neuropathological conditions [116] TheiPSCs technology mediated somatic cell reprogramming ofventricular monocytes results in generation of cells sim-ilar in morphology and functionality with PCs SA notetransplantation of PCs to large animals improves rhythmicheart functions Pacemaker needs very reliable and robustperformance so understanding of transformation process andsite of transplantation are the critical aspect for therapeuticvalidation of iPSCs derived PCs [28] Diabetes is a majorhealth concern in modern world and generation of 120573-cells from adult tissue is challenging Direct reprogrammingof skin cells into pancreatic cells bypassing pluripotencyphase can yield clinical grade 120573-cells This reprogrammingstrategy involves transformation of skin cells into definitiveendodermal progenitors (cDE) and foregut like progenitorcells (cPF) intermediates and subsequent in vitro expansionof these intermediates to become pancreatic 120573-cells (cPB)The first step is chemically complex and can be understood asnonepisomal reprogramming on day one with pluripotencyfactors (OCT4 SOX2 KLF4 and hair pin RNA against p53)then supplementation with GFs and chemical supplementson day seven (EGF bFGF CHIR NECA NaB Par andRG) and two weeks later (Activin-A CHIR NECA NaBand RG) yielding DE and cPF [86] Transplantation of cPByields into glucose stimulated secretion of insulin in diabeticmice defines that such cells can be explored for treatment ofT1DM and T2DM in more personalized manner [86] iPSCsrepresent underrated opportunities for drug industries andclinical research laboratories for development of therapeuticsbut safety concerns might limit transplantation applications(Figure 7 Table 1) [117] Transplantation of human iPSCs intomice gastrula leads to colonization and differentiation of cellsinto three germ layers evidenced with clinical developmentalfat measurements The acceptance of human iPSCs by mice


gastrula suggests that correct timing and appropriate repro-gramming regime might delimit humanmice species barrierUsing this fact of species barrier generation of human organsin closely associated primates might be possible which canbe used for treatment of genetic factors governed diseaseat embryo level itself [118] In summary iPSCs are safe andeffective for treatment of regenerative medicine

8 Stem Cells in Wildlife Conservation

The unstable growth of human population threatens theexistence of wildlife through overexploitation of naturalhabitats and illegal killing of wild animals leading manyspecies to face the fate of being endangered and go forextinction For wildlife conservation the concept of creationof frozen zoo involves preservation of gene pool and germplasm from threatened and endangered species (Figure 8)The frozen zoo tissue samples collection from dead or liveanimal can be DNA sperms eggs embryos gonads skinor any other tissue of the body [119] Preserved tissue can bereprogrammed or transdifferentiated to become other typesof tissues and cells which opens an avenue for conservationof endangered species and resurrection of life (Figure 8) Thegonadal tissue from young individuals harbouring immaturetissue can be matured in vivo and ex vivo for generationof functional gametes Transplantation of SSCs to testis ofmale from the same different species can give rise to sper-matozoa of donor cells [120] which might be used for IVFbased captive breeding of wild animals The most dangerousfact in wildlife conservation is low genetic diversity toofew reproductively capable animals which cannot maintainadequate genetic diversity in wild or captivity Using the edgeof iPSC technology pluripotent stem cells can be generatedfrom skin cells For endangered drillMandrillus leucophaeusand nearly extinct white rhinoceros Ceratotherium simumcottoni iPSC has been generated in 2011 [121] The endan-gered animal drill (Mandrillus leucophaeus) is geneticallyvery close to human and often suffers from diabetes whilerhinos are genetically far removed from other primatesThe progress in iPSCs from the human point of viewmight be transformed for animal research for recapturingreproductive potential and health in wild animals Howeverstem cells based interventions in wild animals are muchmore complex than classical conservation planning andbiomedical research has to face Conversion of iPSC intoegg or sperm can open the door for generation of IVFbased embryo those might be transplanted in womb of livecounterparts for propagation of population Recently iPSCshave been generated for snow leopard (Panthera uncia)native to mountain ranges of central Asia which belongsto cat family this breakthrough has raised the possibilitiesfor cryopreservation of genetic material for future cloningand other assisted reproductive technology (ART) applica-tions for the conservation of cat species and biodiversityGeneration of leopard iPSCs has been achieved throughretroviral-system based genomic integration of OCT4 SOX2KLF4 cMYC and NANOGThese iPSCs from snow leopardalso open an avenue for further transformation of iPSCs

into gametes [122] The in vivo maturation of grafted tissuedepends both on age and on hormonal status of donor tissueThese facts are equally applicable to accepting host Ectopicxenografts of cryopreserved testis tissue from Indian spotteddeer (Moschiola indica) to nude mice yielded generation ofspermatocytes [123] suggesting that one-day procurementof functional sperm from premature tissue might becomea general technique in wildlife conservation In summarytissue biopsies from dead or live animals can be used forgeneration of iPSCs and functional gametes those can beused in assisted reproductive technology (ART) for wildlifeconservation

9 Future Perspectives

The spectacular progress in the field of stem cells researchrepresents great scope of stem cells regenerative therapeuticsIt can be estimated that by 2020 or so we will be able toproduce wide array of tissue organoid and organs fromadult stem cells Inductions of pluripotency phenotypes interminally differentiated adult cells have better therapeuticfuture than ESCs due to least ethical constraints with adultcells In the coming future there might be new pharmaceu-tical compounds those can activate tissue specific stem cellspromote stem cells to migrate to the side of tissue injury andpromote their differentiation to tissue specific cells Exceptfew countries the ongoing financial and ethical hindranceon ESCs application in regenerative medicine have morechance for funding agencies to distribute funding for the leastrisky projects on UCSCs BMSCs and TSPSCs from biopsiesThe existing stem cells therapeutics advancements are moreexperimental and high in cost due to that application onbroad scale is not feasible in current scenario In the nearfuture the advancements of medical science presume usingstem cells to treat cancer muscles damage autoimmunedisease and spinal cord injuries among a number of impair-ments and diseases It is expected that stem cells therapieswill bring considerable benefits to the patients suffering fromwide range of injuries and diseaseThere is high optimism foruse of BMSCs TSPSCs and iPSCs for treatment of variousdiseases to overcome the contradictions associated withESCs For advancement of translational application of stemcells there is a need of clinical trials which needs fundingrejoinder from both public and private organizations Thecritical evaluation of regulatory guidelines at each phase ofclinical trial is a must to comprehend the success and efficacyin time frame

Abbreviations

ESCs Embryonic stem cellsTSPSCs Tissue specific progenitor stem cellsUCSCs Umbilical cord stem cellsBMSCs Bone marrow stem cellsiPSCs Induced pluripotent stem cellsMSCs Mesenchymal stem cellsWJ-MSCs Whartonrsquos jelly mesenchymal stem cellsHSCs Hematopoietic stem cells


RGCs Retinal ganglion cellsT1DM Type I diabetes mellitusT2DM Type 2 diabetes mellitusA1AD 120572-1 antitrypsin deficiencyCOPD Chronic obstructive pulmonary diseaseHLA Human leukocyte antigenMHC Major histocompatibility complex3D Three-dimensionalSCI Spinal cord injuryARMD Age-related macular degenerationRPE Retinal pigment epitheliumPXR Pregnane X receptorDPSCs Dental pulp stem cellsGFAP Glial fibrillary acidic proteinAtoh1 Activation of transcription factor atonal

homologue 1NEC Necrotizing enterocolitisDMD Duchene muscular dystrophyPDGF Placental derived growth factorPEG Polyethylene glycolSSCs Spermatogonial stem cellsAdSCs Adipose derived stem cellsHSCs Hematopoietic stem cellsAFSCs Amniotic fluid stem cellsVEGF Vascular endothelial growth factorUCB Umbilical cord bloodSLEDAI Systematic lupus erythematosus (SLE) dis-

ease activity indexHIV-1 Human immunodeficiency virus-1GM-HSPCs Genetically modified hematopoietic stem

and progenitor cellsTh T helperLA Lipoic acidTRC Tissue repair cellsBM-MSCs Bone marrow mesenchymal stem cellsPBSCs Peripheral blood stem cellsG-CSF Granulocyte-colony stimulating factorSERPINA1 Serpin peptidase inhibitor clade Amember

1ASD Autism spectrum disorderINs InterneuronsGABAergic Υ-amino butyric acid secretingNPCs Neuronal progenitor cellsiTSCs Independent trophoblast stem-like cellshCS Human cortical spheroidsCMs CardiomyocytesALD AdrenoleukodystrophyMLD Metachromatic leukodystrophyTSD Tay-Sachs diseaseALS Amyotrophic lateral sclerosisTBI Traumatic brain injuriesAD Alzheimerrsquos diseaseNSCs Neuronal stem cellsSID Severe immune deficiency

Competing Interests

There are no competing interests associated with this paper

Acknowledgments

Dr Anuradha Reddy from Centre for Cellular andMolecularBiologyHyderabad andMrs SaritaKumari fromDepartmentof Yoga Science BU Bhopal India are acknowledged fortheir critical suggestions and comments on paper

References

[1] C Mason and P Dunnill ldquoA brief definition of regenerativemedicinerdquo Regenerative Medicine vol 3 no 1 pp 1ndash5 2008

[2] L A Fortier ldquoStem cells classifications controversies andclinical applicationsrdquo Veterinary Surgery vol 34 no 5 pp 415ndash423 2005

[3] K Takahashi and S Yamanaka ldquoInduction of pluripotent stemcells from mouse embryonic and adult fibroblast cultures bydefined factorsrdquo Cell vol 126 no 4 pp 663ndash676 2006

[4] J Yu M A Vodyanik K Smuga-Otto et al ldquoInduced pluripo-tent stem cell lines derived from human somatic cellsrdquo Sciencevol 318 no 5858 pp 1917ndash1920 2007

[5] M Thomson S J Liu L-N Zou Z Smith A Meissner andS Ramanathan ldquoPluripotency factors in embryonic stem cellsregulate differentiation into germ layersrdquoCell vol 145 no 6 pp875ndash889 2011

[6] E W Petersdorf M Malkki T A Gooley P J Martin and ZGuo ldquoMHC haplotype matching for unrelated hematopoieticcell transplantationrdquoPLoSMedicine vol 4 no 1 article e8 2007

[7] A M Leferink Y C Chng C A van Blitterswijk and LMoroni ldquoDistribution and viability of fetal and adult humanbonemarrow stromal cells in a biaxial rotating vessel bioreactorafter seeding on polymeric 3D additivemanufactured scaffoldsrdquoFrontiers in Bioengineering and Biotechnology vol 3 article 1692015

[8] E A Gubareva S Sjoqvist I V Gilevich et al ldquoOrthotopictransplantation of a tissue engineered diaphragm in ratsrdquoBiomaterials vol 77 pp 320ndash335 2016

[9] I Garzon B Perez-Kohler J Garrido-Gomez et al ldquoEvaluationof the cell viability of human Whartonrsquos Jelly stem cells for usein cell therapyrdquo Tissue Engineering Part C Methods vol 18 no6 pp 408ndash419 2012

[10] P A Thompson T Perera D Marin et al ldquoDouble umbilicalcord blood transplant is effective therapy for relapsed orrefractory Hodgkin lymphomardquo Leukemia amp Lymphoma vol57 no 7 pp 1607ndash1615 2016

[11] S S Nathamgari B Dong F Zhou et al ldquoIsolating single cellsin a neurosphere assay using inertial microfluidicsrdquo Lab on aChipmdashMiniaturisation for Chemistry and Biology vol 15 no 24pp 4591ndash4597 2015

[12] B Ning D K Cheuk A K Chiang P P Lee S Y Ha and GC Chan ldquoAutologous cord blood transplantation for metastaticneuroblastomardquo Pediatric Transplantation vol 20 no 2 pp290ndash296 2015

[13] J AThomson ldquoEmbryonic stem cell lines derived from humanblastocystsrdquo Science vol 282 no 5391 pp 1145ndash1147 1998

[14] M S Hogan D-E Parfitt C J Zepeda-Mendoza M M ShenandD L Spector ldquoTransient pairing of homologousOct4 allelesaccompanies the onset of embryonic stem cell differentiationrdquoCell Stem Cell vol 16 no 3 pp 275ndash288 2015

[15] G Shroff and R Gupta ldquoHuman embryonic stem cells inthe treatment of patients with spinal cord injuryrdquo Annals ofNeurosciences vol 22 no 4 pp 208ndash216 2015


[16] S Zhou A Flamier M Abdouh et al ldquoDifferentiation ofhuman embryonic stem cells into cone photoreceptors throughsimultaneous inhibition of BMP TGF120573 and Wnt signalingrdquoDevelopment vol 142 no 19 pp 3294ndash3306 2015

[17] V M Sluch C-H O Davis V Ranganathan et al ldquoDifferenti-ation of human ESCs to retinal ganglion cells using a CRISPRengineered reporter cell linerdquo Scientific Reports vol 5 ArticleID 16595 2015

[18] Y Shiba S FernandesW-Z Zhu et al ldquoHumanES-cell-derivedcardiomyocytes electrically couple and suppress arrhythmias ininjured heartsrdquo Nature vol 489 no 7415 pp 322ndash325 2012

[19] S Fernandes J J H Chong S L Paige et al ldquoComparison ofhuman embryonic stem cell-derived cardiomyocytes cardio-vascular progenitors and bone marrow mononuclear cells forcardiac repairrdquo StemCell Reports vol 5 no 5 pp 753ndash762 2015

[20] Y Avior G Levy M Zimerman et al ldquoMicrobial-derivedlithocholic acid and vitamin K

2drive the metabolic maturation

of pluripotent stem cells-derived and fetal hepatocytesrdquo Hepa-tology vol 62 no 1 pp 265ndash278 2015

[21] K Cameron B Lucendo-Villarin D Szkolnicka and D C HayldquoSerum-free directed differentiation of human embryonic stemcells to hepatocytesrdquo Methods in Molecular Biology vol 1250pp 105ndash111 2015

[22] M Zhang P Sun Y Wang et al ldquoGeneration of self-renewinghepatoblasts from human embryonic stem cells by chemicalapproachesrdquo Stem Cells Translational Medicine vol 4 no 11 pp1275ndash1282 2015

[23] L Tolosa J Caron Z Hannoun et al ldquoTransplantation ofhESC-derived hepatocytes protects mice from liver injuryrdquoStem Cell Research ampTherapy vol 6 article 246 2015

[24] A Carpentier I Nimgaonkar V Chu Y Xia Z Hu and T JLiang ldquoHepatic differentiation of human pluripotent stem cellsin miniaturized format suitable for high-throughput screenrdquoStem Cell Research vol 16 no 3 pp 640ndash650 2016

[25] J E Bruin N Saber N Braun et al ldquoTreating diet-induceddiabetes and obesity with human embryonic stem cell-derivedpancreatic progenitor cells and antidiabetic drugsrdquo Stem CellReports vol 4 no 4 pp 605ndash620 2015

[26] C Salguero-Aranda R Tapia-Limonchi and G M CahuanaldquoDifferentiation of mouse embryonic stem cells towards func-tional pancreatic beta-cell surrogates through epigenetic regu-lation of Pdx1 by nitric oxiderdquo Cell Transplantation 2016

[27] A Cheng Z Kapacee J Peng et al ldquoCartilage repair usinghuman embryonic stem cell-derived chondroprogenitorsrdquo StemCells Translational Medicine vol 3 no 11 pp 1287ndash1295 2014

[28] VVedantham ldquoNewapproaches to biological pacemakers linksto sinoatrial node developmentrdquo Trends in Molecular Medicinevol 21 no 12 pp 749ndash761 2015

[29] C Greggio F De Franceschi M Figueiredo-Larsen et al ldquoArti-ficial three-dimensional niches deconstruct pancreas develop-ment in vitrordquo Development vol 140 no 21 pp 4452ndash44622013

[30] L YeMA Robertson T LMastracci andRMAnderson ldquoAninsulin signaling feedback loop regulates pancreas progenitorcell differentiation during islet development and regenerationrdquoDevelopmental Biology vol 409 no 2 pp 354ndash369 2016

[31] P D Potdar and Y D Jethmalani ldquoHuman dental pulp stemcells applications in future regenerative medicinerdquoWorld Jour-nal of Stem Cells vol 7 no 5 pp 839ndash851 2015

[32] K M Ellis D C OrsquoCarroll M D Lewis G Y Rychkov andS A Koblar ldquoNeurogenic potential of dental pulp stem cells

isolated from murine incisorsrdquo Stem Cell Research amp Therapyvol 5 article 30 2014

[33] M M Acharya V Martirosian N N Chmielewski et al ldquoStemcell transplantation reverses chemotherapy-induced cognitivedysfunctionrdquo Cancer Research vol 75 no 4 pp 676ndash686 2015

[34] K Mizutari M Fujioka M Hosoya et al ldquoNotch inhibitioninduces cochlear hair cell regeneration and recovery of hearingafter acoustic traumardquo Neuron vol 77 no 1 pp 58ndash69 2013

[35] B R Kuo E M Baldwin W S Layman M M Taketo and JZuo ldquoIn vivo cochlear hair cell generation and survival by coac-tivation of 120573-catenin and Atoh1rdquo The Journal of Neurosciencevol 35 no 30 pp 10786ndash10798 2015

[36] S A Shaffiey H Jia T Keane et al ldquoIntestinal stem cell growthand differentiation on a tubular scaffoldwith evaluation in smalland large animalsrdquo Regenerative Medicine vol 11 no 1 pp 45ndash61 2016

[37] D H Scoville T Sato X C He and L Li ldquoCurrent viewintestinal stem cells and signalingrdquo Gastroenterology vol 134no 3 pp 849ndash864 2008

[38] X Yin H F Farin J H Van Es H Clevers R Langer andJ M Karp ldquoNiche-independent high-purity cultures of Lgr5+intestinal stem cells and their progenyrdquo Nature Methods vol 11no 1 pp 106ndash112 2014

[39] B R Ksander P E Kolovou B J Wilson et al ldquoABCB5 is alimbal stem cell gene required for corneal development andrepairrdquo Nature vol 511 no 7509 pp 353ndash357 2014

[40] S Ahmad ldquoConcise review limbal stem cell deficiency dys-function and distressrdquo Stem Cells Translational Medicine vol1 no 2 pp 110ndash115 2012

[41] C Fuoco R Rizzi A Biondo et al ldquoIn vivo generationof a mature and functional artificial skeletal musclerdquo EMBOMolecular Medicine vol 7 no 4 pp 411ndash422 2015

[42] S E Berry ldquoConcise review mesoangioblast and mesenchymalstem cell therapy for muscular dystrophy progress challengesand future directionsrdquo Stem Cells Translational Medicine vol 4no 1 pp 91ndash98 2015

[43] L Simon G C Ekman N Kostereva et al ldquoDirect transdiffer-entiation of stemprogenitor spermatogonia into reproductiveand nonreproductive tissues of all germ layersrdquo Stem Cells vol27 no 7 pp 1666ndash1675 2009

[44] S M Cronk M R Kelly-Goss H C Ray et al ldquoAdipose-derived stem cells from diabetic mice show impaired vascularstabilization in a murine model of diabetic retinopathyrdquo StemCells Translational Medicine vol 4 no 5 pp 459ndash467 2015

[45] B Mead M Berry A Logan R A H Scott W Leadbeater andB A Scheven ldquoStem cell treatment of degenerative eye diseaserdquoStem Cell Research vol 14 no 3 pp 243ndash257 2015

[46] M Kessler K Hoffmann V Brinkmann et al ldquoThe Notchand Wnt pathways regulate stemness and differentiation inhuman fallopian tube organoidsrdquo Nature Communications vol6 article 8989 2015

[47] H Nagata M Ii E Kohbayashi M Hoshiga T Hanafusaand M Asahi ldquoCardiac adipose-derived stem cells exhibit highdifferentiation potential to cardiovascular cells in C57BL6micerdquo Stem Cells Translational Medicine vol 5 no 2 pp 141ndash151 2016

[48] L Chen F Qin M Ge Q Shu and J Xu ldquoApplication ofadipose-derived stem cells in heart diseaserdquo Journal of Cardio-vascular Translational Research vol 7 no 7 pp 651ndash663 2014

[49] S K Steinbach and M Husain ldquoVascular smooth muscle celldifferentiation from human stemprogenitor cellsrdquo Methodsvol 101 pp 85ndash92 2016


[50] M Dominici K Le Blanc I Mueller et al ldquoMinimal crite-ria for defining multipotent mesenchymal stromal cells TheInternational Society for Cellular Therapy position statementrdquoCytotherapy vol 8 no 4 pp 315ndash317 2006

[51] A K Sharma M I Bury A J Marks et al ldquoA nonhumanprimate model for urinary bladder regeneration using autolo-gous sources of bonemarrow-derivedmesenchymal stem cellsrdquoSTEM CELLS vol 29 no 2 pp 241ndash250 2011

[52] M Oshima and T Tsuji ldquoWhole tooth regeneration as afuture dental treatmentrdquo Advances in Experimental Medicineand Biology vol 881 pp 255ndash269 2015

[53] C Csaki U Matis A Mobasheri H Ye and M ShakibaeildquoChondrogenesis osteogenesis and adipogenesis of caninemesenchymal stem cells a biochemical morphological andultrastructural studyrdquo Histochemistry and Cell Biology vol 128no 6 pp 507ndash520 2007

[54] I Ribitsch J Burk U Delling et al ldquoBasic science and clinicalapplication of stem cells in veterinary medicinerdquo Advances inBiochemical EngineeringBiotechnology vol 123 pp 219ndash2632010

[55] B Sen Z Xie G Uzer et al ldquoIntranuclear actin regulatesosteogenesisrdquo STEMCELLS vol 33 no 10 pp 3065ndash3076 2015

[56] S G Brown R J Harman and L L Black ldquoAdipose-derivedstem cell therapy for severe muscle tears in working Germanshepherds two case reportsrdquo Stem Cell Discovery vol 2 no 2pp 41ndash44 2012

[57] R D Levit N Landazuri E A Phelps et al ldquoCellular encapsu-lation enhances cardiac repairrdquo Journal of the American HeartAssociation vol 2 no 5 Article ID e000367 2013

[58] B-J Lin J Wang Y Miao et al ldquoCytokine loaded layer-by-layer ultrathin matrices to deliver single dermal papilla cellsfor spot-by-spot hair follicle regenerationrdquo Journal of MaterialsChemistry B vol 4 no 3 pp 489ndash504 2016

[59] O M Benavides A R Brooks S K Cho J Petsche Connell RRuano and J G Jacot ldquoIn situ vascularization of injectable fib-rinpoly(ethylene glycol) hydrogels by human amniotic fluid-derived stem cellsrdquo Journal of Biomedical Materials ResearchPart A vol 103 no 8 pp 2645ndash2653 2015

[60] KWolfrum YWang A Prigione K Sperling H Lehrach andJ Adjaye ldquoThe LARGE principle of cellular reprogramminglost acquired and retained gene expression in foreskin andamniotic fluid-derived human iPS cellsrdquo PLoS ONE vol 5 no10 Article ID e13703 2010

[61] J E Wagner Jr C G Brunstein A E Boitano et al ldquoPhaseIII trial of stemregenin-1 expanded umbilical cord bloodhematopoietic stem cells supports testing as a stand-alone graftrdquoCell Stem Cell vol 18 no 1 pp 144ndash155 2016

[62] J Hu X Yu Z Wang et al ldquoLong term effects of the implan-tation of Whartonrsquos jelly-derived mesenchymal stem cells fromthe umbilical cord for newly-onset type 1 diabetes mellitusrdquoEndocrine Journal vol 60 no 3 pp 347ndash357 2013

[63] X Liu P Zheng X Wang et al ldquoA preliminary evaluation ofefficacy and safety of Whartonrsquos jelly mesenchymal stem celltransplantation in patients with type 2 diabetes mellitusrdquo StemCell Research ampTherapy vol 5 no 2 article 57 2014

[64] D Wang J Li Y Zhang et al ldquoUmbilical cord mesenchymalstem cell transplantation in active and refractory systemic lupuserythematosus AMulticenter Clinical StudyrdquoArthritis ResearchandTherapy vol 16 no 2 article R79 2014

[65] M L Escolar M D Poe J M Provenzale et al ldquoTransplanta-tion of umbilical-cord blood in babies with infantile Krabbersquos

diseaserdquoThe New England Journal of Medicine vol 352 no 20pp 2069ndash2081 2005

[66] M Jurga A W Lipkowski B Lukomska et al ldquoGeneration offunctional neural artificial tissue from human umbilical cordblood stem cellsrdquo Tissue Engineering Part C Methods vol 15no 3 pp 365ndash372 2009

[67] J Ehrhart D Darlington N Kuzmin-Nichols et al ldquoBiodis-tribution of infused human umbilical cord blood cells inAlzheimerrsquos disease-like murine modelrdquo Cell Transplantationvol 25 no 1 pp 195ndash199 2016

[68] G-Y Park D R Kwon and S C Lee ldquoRegeneration offull-thickness rotator cuff tendon tear after ultrasound-guidedinjection with umbilical cord blood-derivedmesenchymal stemcells in a Rabbit modelrdquo Stem Cells Translational Medicine vol4 no 11 pp 1344ndash1351 2015

[69] C-W Ha Y-B Park J-Y Chung and Y-G Park ldquoCartilagerepair using composites of humanumbilical cord blood-derivedmesenchymal stem cells and hyaluronic acid hydrogel in aminipig modelrdquo Stem Cells Translational Medicine vol 4 no9 pp 1044ndash1051 2015

[70] Y P Fan C Hsia K Tseng et al ldquoThe therapeutic potentialof human umbilical mesenchymal stem cells from Whartonrsquosjelly in the treatment of rat peritoneal dialysis-induced fibrosisrdquoStem Cells Translational Medicine vol 5 no 2 pp 235ndash2472016

[71] S Gaballa N Palmisiano O Alpdogan et al ldquoA two-stephaploidentical versus a two-step matched related allogeneicmyeloablative peripheral blood stem cell transplantationrdquo Biol-ogy of Blood andMarrow Transplantation vol 22 no 1 pp 141ndash148 2016

[72] D L DiGiusto R Stan A Krishnan H Li J J Rossi and JA Zaia ldquoDevelopment of hematopoietic stem cell based genetherapy for HIV-1 infection considerations for proof of conceptstudies and translation to standard medical practicerdquo Virusesvol 5 no 11 pp 2898ndash2919 2013

[73] E Herrera-Carrillo and B Berkhout ldquoBone marrow genetherapy for HIVAIDSrdquo Viruses vol 7 no 7 pp 3910ndash39362015

[74] K R Machlus and J E Italiano Jr ldquoThe incredible journeyfrom megakaryocyte development to platelet formationrdquo TheJournal of Cell Biology vol 201 no 6 pp 785ndash796 2013

[75] C A Di Buduo L S Wray L Tozzi et al ldquoProgrammable3D silk bone marrow niche for platelet generation ex vivo andmodeling of megakaryopoiesis pathologiesrdquo Blood vol 125 no14 pp 2254ndash2264 2015

[76] S Paradells I ZipancicMMMartınez-Losa et al ldquoLipoic acidand bonemarrow derived cells therapy induce angiogenesis andcell proliferation after focal brain injuryrdquo Brain Injury vol 29no 3 pp 380ndash395 2015

[77] D Kaigler G Pagni C H Park et al ldquoStem cell therapyfor craniofacial bone regeneration a randomized controlledfeasibility trialrdquo Cell Transplantation vol 22 no 5 pp 767ndash7772013

[78] Y Tsai B Lu B Bakondi et al ldquoHuman iPSC-derived neuralprogenitors preserve vision in an AMD-like modelrdquo STEMCELLS vol 33 no 8 pp 2537ndash2549 2015

[79] J Yang B Cai P Glencer Z Li X Zhang and X Li ldquoInducedpluripotent stem cells and outer retinal diseaserdquo Stem CellsInternational vol 2016 Article ID 2850873 6 pages 2016

[80] S E Howden J P Maufort B M Duffin A G Elefanty E GStanley and J AThomson ldquoSimultaneous reprogramming and


gene correction of patient fibroblastsrdquo Stem Cell Reports vol 5no 6 pp 1109ndash1118 2015

[81] G Colasante G Lignani A Rubio et al ldquoRapid conversion offibroblasts into functional forebrain GABAergic interneuronsby direct genetic reprogrammingrdquo Cell Stem Cell vol 17 no 6pp 719ndash734 2015

[82] R F Hunt and S C Baraban ldquoInterneuron transplantation asa treatment for epilepsyrdquo Cold Spring Harbor Perspectives inMedicine vol 5 no 12 Article ID a022376 2015

[83] A M Pasca S A Sloan L E Clarke et al ldquoFunctional corticalneurons and astrocytes from human pluripotent stem cells in3D culturerdquo Nature Methods vol 12 no 7 pp 671ndash678 2015

[84] J Mariani G Coppola P Zhang et al ldquoFOXG1-dependentdysregulation of GABAglutamate neuron differentiation inautism spectrum disordersrdquo Cell vol 162 no 2 pp 375ndash3902015

[85] A A Wilson L Ying M Liesa et al ldquoEmergence of astage-dependent human liver disease signature with directeddifferentiation of alpha-1 antitrypsin-deficient iPS cellsrdquo StemCell Reports vol 4 no 5 pp 873ndash885 2015

[86] S Zhu H A Russ X Wang et al ldquoHuman pancreatic beta-likecells converted from fibroblastsrdquo Nature Communications vol7 Article ID 10080 2016

[87] B R Dye D R Hill M A Ferguson et al ldquoIn vitro generationof human pluripotent stem cell derived lung organoidsrdquo eLifevol 4 Article ID e05098 pp 1ndash25 2015

[88] A Kambal G Mitchell W Cary et al ldquoGeneration of HIV-1resistant and functional macrophages from hematopoietic stemcell-derived induced pluripotent stem cellsrdquoMolecularTherapyvol 19 no 3 pp 584ndash593 2011

[89] Z Jiang Y Han and X Cao ldquoInduced pluripotent stem cell(iPSCs) and their application in immunotherapyrdquo Cellular andMolecular Immunology vol 11 no 1 pp 17ndash24 2014

[90] T Squillaro G Peluso and U Galderisi ldquoClinical trials withmesenchymal stem cells an updaterdquo Cell Transplantation vol25 no 5 pp 829ndash848 2016

[91] V Volarevic J Nurkovic N Arsenijevic and M StojkovicldquoConcise review therapeutic potential of mesenchymal stemcells for the treatment of acute liver failure and cirrhosisrdquo STEMCELLS vol 32 no 11 pp 2818ndash2823 2014

[92] S Patel P T Yin H Sugiyama and K-B Lee ldquoInducing stemcell myogenesis using nanoscriptrdquo ACS Nano vol 9 no 7 pp6909ndash6917 2015

[93] S Dameshghi A Zavaran-Hosseini S Soudi F J Shirazi SNojehdehi and S M Hashemi ldquoMesenchymal stem cells altermacrophage immune responses to Leishmania major infectionin both susceptible and resistance micerdquo Immunology Lettersvol 170 pp 15ndash26 2016

[94] S Shahrokhi F Menaa K Alimoghaddam C McGuckin andM Ebtekar ldquoInsights and hopes in umbilical cord blood stemcell transplantationsrdquo Journal of Biomedicine and Biotechnologyvol 2012 Article ID 572821 11 pages 2012

[95] S Rentas N T Holzapfel M S Belew et al ldquoMusashi-2attenuates AHR signalling to expand human haematopoieticstem cellsrdquo Nature vol 532 no 7600 pp 508ndash511 2016

[96] H Lu Y Chen Q Lan et al ldquoFactors that influence a motherrsquoswillingness to preserve umbilical cord blood a survey of5120 Chinese mothersrdquo PLoS ONE vol 10 no 12 Article IDe0144001 2015

[97] A Rosemann ldquoWhy regenerative stem cell medicine progressesslower than expectedrdquo Journal of Cellular Biochemistry vol 115no 12 pp 2073ndash2076 2014

[98] E Gluckman G Koegler and V Rocha ldquoHuman leukocyteantigen matching in cord blood transplantationrdquo Seminars inHematology vol 42 no 2 pp 85ndash90 2005

[99] R S Mehta K Rezvani A Olson et al ldquoNovel techniques forex vivo expansion of cord blood clinical trialsrdquo Frontiers inMedicine vol 2 article 89 2015

[100] Y Wang F Chen B Gu G Chen H Chang and D WuldquoMesenchymal stromal cells as an adjuvant treatment for severelate-onset hemorrhagic cystitis after allogeneic hematopoieticstem cell transplantationrdquo Acta Haematologica vol 133 no 1pp 72ndash77 2015

[101] B Gokcinar-Yagci O Ozyuncu and B Celebi-Saltik ldquoIsolationcharacterisation and comparative analysis of human umbilicalcord vein perivascular cells and cord blood mesenchymal stemcellsrdquo Cell and Tissue Banking vol 17 no 2 pp 345ndash352 2015

[102] J Liang FWang DWang et al ldquoTransplantation ofmesenchy-mal stem cells in a laryngeal carcinoma patient with radiationmyelitisrdquo Stem Cell Research and Therapy vol 6 article 2132015

[103] J Kumar V Kale and L Limaye ldquoUmbilical cord blood-derivedCD11c+ dendritic cells could serve as an alternative allogeneicsource of dendritic cells for cancer immunotherapyrdquo Stem CellResearch ampTherapy vol 6 article 184 2015

[104] C Zhang Y Zhu Y Zhang L Gao N Zhang and H FengldquoTherapeutic potential of umbilical cord mesenchymal stemcells for inhibiting myofibroblastic differentiation of irradiatedhuman lung fibroblastsrdquo The Tohoku Journal of ExperimentalMedicine vol 236 no 3 pp 209ndash217 2015

[105] L Fu Y Liu D Zhang J Xie HGuan andT Shang ldquoBeneficialeffect of human umbilical cord-derived mesenchymal stemcells on an endotoxin-induced rat model of preeclampsiardquoExperimental and Therapeutic Medicine vol 10 no 5 pp 1851ndash1856 2015

[106] S Osone T Imamura Y Fukushima-Nakase et al ldquoCasereports of severe congenital neutropenia treated with unrelatedcord blood transplantation with reduced-intensity condition-ingrdquo Journal of Pediatric HematologyOncology vol 38 no 1 pp49ndash52 2016

[107] M-Y Chang T-THuang C-H Chen B Cheng S-MHwangand P C H Hsieh ldquoInjection of human cord blood cells withhyaluronan improves postinfarction cardiac repair in pigsrdquoStem Cells Translational Medicine vol 5 no 1 pp 56ndash66 2016

[108] G S Travlos ldquoNormal structure function and histology of thebonemarrowrdquo Toxicologic Pathology vol 34 no 5 pp 548ndash5652006

[109] E Gschweng S De Oliveira and D B Kohn ldquoHematopoieticstem cells for cancer immunotherapyrdquo Immunological Reviewsvol 257 no 1 pp 237ndash249 2014

[110] R SinghMahla ldquoHIV-1 Infection the functional importance ofSDF1 CCR2 and CCR5 in protection and therapeuticsrdquo HealthCare Current Reviews vol 3 article 150 2015

[111] T Miyamoto and H Nakauchi ldquoGeneration of functionalorgans from pluripotent stem cellsrdquo The Japanese Journal ofClinical Hematology vol 56 pp 2213ndash2219 2015

[112] RMorizane A Q Lam B S Freedman S KishiM T Valeriusand J V Bonventre ldquoNephron organoids derived from humanpluripotent stem cells model kidney development and injuryrdquoNature Biotechnology vol 33 no 11 pp 1193ndash1200 2015

[113] S P Lukashyk V M Tsyrkunov Y I Isaykina et al ldquoMes-enchymal bone marrow-derived stem cells transplantation inpatients with HCV related liver cirrhosisrdquo Journal of Clinicaland Translational Hepatology vol 2 no 4 pp 217ndash221 2014


[114] M Takasato P X Er H S Chiu et al ldquoKidney organoids fromhuman iPS cells contain multiple lineages and model humannephrogenesisrdquo Nature vol 526 no 7574 pp 564ndash568 2015

[115] H Benchetrit S Herman N Van Wietmarschen et al ldquoExten-sive nuclear reprogramming underlies lineage conversion intofunctional trophoblast stem-like cellsrdquoCell StemCell vol 17 no5 pp 543ndash556 2015

[116] J Lu X Zhong H Liu et al ldquoGeneration of serotonin neuronsfrom human pluripotent stem cellsrdquo Nature Biotechnology vol34 no 1 pp 89ndash94 2016

[117] K Takahashi and S Yamanaka ldquoInduced pluripotent stem cellsin medicine and biologyrdquo Development vol 140 no 12 pp2457ndash2461 2013

[118] V L Mascetti and R A Pedersen ldquoHuman-mouse chimerismvalidates human stem cell pluripotencyrdquo Cell Stem Cell vol 18no 1 pp 67ndash72 2016

[119] P Comizzoli and W V Holt ldquoRecent advances and prospectsin germplasm preservation of rare and endangered speciesrdquoAdvances in Experimental Medicine and Biology vol 753 pp331ndash356 2014

[120] I Dobrinski and A J Travis ldquoGerm cell transplantation forthe propagation of companion animals non-domestic andendangered speciesrdquo Reproduction Fertility and Developmentvol 19 no 6 pp 732ndash739 2007

[121] I F Ben-Nun S C Montague M L Houck et al ldquoInducedpluripotent stem cells from highly endangered speciesrdquo NatureMethods vol 8 no 10 pp 829ndash831 2011

[122] R Verma M K Holland P Temple-Smith and P J VermaldquoInducing pluripotency in somatic cells from the snow leopard(Panthera uncia) an endangered felidrdquo Theriogenology vol 77no 1 pp 220ndash228e2 2012

[123] L Pothana HMakala L Devi V P Varma and S Goel ldquoGermcell differentiation in cryopreserved immature Indian spottedmouse deer (Moschiola indica) testes xenografted onto micerdquoTheriogenology vol 83 no 4 pp 625ndash633 2015

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Healthy donor

Patient

(1) ESCs (2) TSPSCs (3) MSCs (4) UCSCs(5) BMSCs (6) IPSCs

Promises of stem cells in regenerative medicines

(1)

(2)

(3)

(4)

(5)

(6)

(i) T1DM and T2DM treatment(ii) SLE (autoimmune disease) treatment

(iii) Application for HI treatment(iv) Krabbersquos disease treatment(v) Hematopoiesis in neuroblastoma

(i) Improvement of spinal cord injury(ii) Regeneration of retinal sheet

(iii) Generation of retinal ganglion cells(iv) Healing of heart defects(v) Hepatic cell formation

(vii) Cartilage lesion treatment(viii) Regeneration of pacemaker

(ix) In vitro gametogenesis

(i) Regeneration of kidney tissue(ii) Vision restoration in AMD(iii) Treatment of placental defects (iv) Treatment of brain cortex defects(v) ASD and autism treatment

(vi) Treatment of liver and lung disease(vii) Generation of serotonin neurons(viii) Regeneration of pacemaker

(i) Treatment of diabetes and retinopathy (ii) Neurodental therapeutic applications

(iii) Restoration of cognitive functions(iv) Brain and cancer treatment (v) Ear acoustic function restoration

(vi) Regeneration of intestinal mucosa (vii) Treatment of vision defects

(viii) Muscle regeneration(ix) Regeneration of fallopian tube

(i) Regeneration of bladder tissue(ii) Muscle regeneration

(iii) Regeneration of teeth tissue(iv) Healing of orthopedic injuries (v) Recovery from muscle injuries

(vi) Hear scar repair after attack

(i) Treatment of anemia and blood cancer(ii) Retroviral therapy

(iii) Correction of neuronal defects(iv) Generation of functional platelets(v) Alveolar bone regeneration

(vi) Regeneration of diaphragm tissue

(vi) Formation of insulin secreting 120573-cells

Figure 1 Promises of stem cells in regenerative medicine the six classes of stem cells that is embryonic stem cells (ESCs) tissue specificprogenitor stem cells (TSPSCs) mesenchymal stem cells (MSCs) umbilical cord stem cells (UCSCs) bone marrow stem cells (BMSCs) andinduced pluripotent stem cells (iPSCs) have many promises in regenerative medicine and disease therapeutics

immune suppressant is recommended [6] Stem cells expressmajor histocompatibility complex (MHC) receptor in lowand secret chemokine that recruitment of endothelial andimmune cells is enabling tissue tolerance at graft site [6]The current stem cell regenerative medicine approaches arefounded onto tissue engineering technologies that combinethe principles of cell transplantation material science andmicroengineering for development of organoid those canbe used for physiological restoration of damaged tissue andorgans The tissue engineering technology generates nascenttissue on biodegradable 3D-scaffolds [7 8]The ideal scaffoldssupport cell adhesion and ingrowths mimic mechanics oftarget tissue support angiogenesis and neovascularisationfor appropriate tissue perfusion and being nonimmuno-genic to host do not require systemic immune suppres-sant [9] Stem cells number in tissue transplant impactsupon regenerative outcome [10] in that case prior ex vivoexpansion of transplantable stem cells is required [11] Forsuccessful regenerative outcomes transplanted stem cellsmust survive proliferate and differentiate in site specific

manner and integrate into host circulatory system [12] Thisreview provides framework of most recent (Table 1 Figures1ndash8) advancement in transplantation and tissue engineeringtechnologies of ESCs TSPSCs MSCs UCSCs BMSCs andiPSCs in regenerativemedicine Additionally this review alsodiscusses stem cells as the tool of regenerative applications inwildlife conservation

2 ESCs in Regenerative Medicine

For the first time in 1998 Thomson isolated human ESCs(hESCs) [13] ESCs are pluripotent in their nature and cangive rise to more than 200 types of cells and promises forthe treatment of any kinds of disease [13] The pluripo-tency fate of ESCs is governed by functional dynamics oftranscription factors OCT4 SOX2 NANOG and so forthwhich are termed as pluripotency factors The two allelesof the OCT4 are held apart in pluripotency state in ESCsphase through homologues pairing during embryogenesis


ble1Ap

plicationof

stem

cells

inregenerativ

emedicineste

mcells

(ESC

sTS

PSCs

MSC

sUCS

CsB

MSC

sandiPSC

s)have

diverseapplications

intissueregeneratio

nanddisease

therapeutic

s

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

ESCs

Spinalcord

injurie

sInfection

cancerand

accidents

ESCs

transplantationto

injury

site

ESCs

andsecreted

vasculogenicand

neurogenicfactor

supp

orttissue

homing

Regeneratio

nof

spinaltissuea

ndim

proved

balancea

ndsensation

[15]

ARM

Dand

glaucoma

Macular

cones

degeneratio

n

ESCs

-derived

conesa

ndRG

Cstransplantationto

eye

COCO

(activatingTG

F-120573B

MPand

Wnt)amp

BRN3(kno

ck-in

byCR

ISPE

R-Ca

s9)m

akeE

SCsb

ecom

econesa

ndRG

Csform

cells

sheetamp

neuron

alconn

ectio

n

Recovery

from

ARM

Dandmacular

defectsamp

resto

ratio

nof

visio

n[1617]

Cardiovascular

disease

Diabetesdrugs

genetic

factor

andlifes

tyle

ESCs

-derived

CMsamp

biom

aterialcoaxedES

Cs

Cardiomyocytese

xpressGCa

MP3


ox3

differentiatesE

SCsintoSA

NPC

s

Supp

resses

heartarrhythmiasCM

sele

ctroph

ysiologically

integratetoheart

aspacemaker

[181928]

Liverinjuries

Toxinsdrugs

genetic

factors

andinfection

Transplantationof

ESCs

-derived

hepatocytes

ESCs

-hepatocytec

onversionismarked

with

expressio

nof

Cytp450PX

RCY

PA4amp

29H

NF4

-120572and

UGTA

1cells

intransplant

repo

pulateinjured

liver

tissue

Regeneratio

nof

liver

tissuec

anbe

used

asmod

elforscreening

ofdrugs

[202324]

Diabetes

Lifesty

leheart

defectsand

genetic

s

Transplantationof

ESCs

-derived

PPCs

Progenito

rs(C

D24+

CD49+

ampCD

133+)


secreteinsulin

andexpressP

DX1G

CKand

GLU

T2

Improvem


esity

canbe

used

fortreatmento

fT1D

Mand

T2DM

[2526]

Oste

oarthritis

Whencartilage

tissuew

ears

away

Transplantationof

chon

drocytes

organo

ids

Chon

drocytes

(SOX9+

ampcollagen-II+

)form

cells

aggregateamp

remainactiv

efor

12wks


Regeneratio

nof

cartilage

tissuec

anbe

used

fortreatmento

finjuriesfaced

byathletes

[27]

TSPS

Cs

Diabetes

Lifesty

leand

genetic

factors

Transplantationof

SCs

deriv

edPP

Csorgano

idPP

Csneed

niches

uppo

rted

activ

eFGFamp

Notch

signalling

tobecome120573

-cell

PPCs


treatT1DM

ampT2

DM

[252930]

Neurodental

prob

lems

Accidentsage

andgenetic

factors

Transplantationof

DSP

SCsa

sneurons

Neurons

expressn

estin

GFA

P120573III-tubu

linand

L-type

Ca2+

channels


treatmento

fneurod

entalabn

ormalities

[3132]

Acou

sticp

roblem

sAgenoise

drugsand

infection

IESC

sIESC

s-deriv

edhaircells


shutsN

otch

by120573-catenin

ampAtoh

1inlrg

5+IESC

stobe

haircells


resto

ratio

nof

acou

sticfunctio

ns[3435]

Intestinal

degeneratio

n

Geneticfactors

andfood

borne

infections

IPCs

deriv

edcrypt-v

illi

organo

idtransplantation

M120601m

yofib

roblasts

andbacteriasig

nals

IPCs

tobe

crypt-v

illiorganoidtissue

Regeneratio

nof

gobletmucosac

antre

atintestinaldefects

[36ndash

38]

Cornealdiseases

Burnsgenetic

sand

inflammation

LPSC

stransplantatio

nto

cornealtissue

LPSC

sintransplant

markedby

ABC

B5differentiateinto

maturec

ornea

Regeneratio

nof

cornealtissue

might

treat

multip

leeyed

isease

[3940

]

Muscular

deform

ities

Infection

drugs

and

autoim

mun

ity

Transplantationof

PEG

fibrin

ogen

coaxed

MABs

PDGFfro

mMABs

attractvasculogenic

andneurogeniccells

totransplant

site

Muscle

fibril

regeneratio

nskeletal

muscle

defectstreatment

[4142]

Eyed

iseaseamp

retin

opathy

Toxinsburns

andgenetic

factors

AdSC

sintravitre

altransplantation

AdSC

sfrom

healthydo

norp

rodu

cehigh

ervasoprotectiv

efactors

Resto

ratio

nof

vascularisa

tion

diabetic

retin

opathy

treatment

[4445]

Cardiac

dysfu

nctio

ns

Agegenetic

factorsand

toxins

Syste

micinfusio

nof

CA-AdS

Csmyocardium

CA-AdS

Csto

epith

elium

differentiatio

nares

uperiortoAd

SCs

Regeneratio

nof

ischemicmyocardium

[4748]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

MSC

s

Bladder

deform

ities

Cystitiscancer

andinfection

Transplantationof

BD-M

SCstobladder

BDMSC

s(CD

105+C

D73+

CD34minus

and

CD45minus

)with



mdifferent

originsM

SCs

[5051]

Dentalproblem

sInfection

cancer

ageand

accidents

Transplantso

fEMSC

s+DSC

sbiopo

lymer

tissue

EMSC

-DSC

sand


biop

olym

ergive

risetomatureteeth

units

Regeneratio

nof

oraltissuea

ndapplicationin

perio

dontics

[3152]

Bone

degeneratio

nInjurie

sand

tumor

autoim

mun

ity

CoaxedMSC

stransplant

ampMSC

sinfusion

Actin

mod

ellin

gby

cytochalasin-D

transfo

rmsM

SCsintoosteob

lasts

Regeneratio

nof

bonesredu

ctionin

injury

pain

[53ndash55]

Muscle

degeneratio

nGeneticfactors

andworkstr

ess

CoaxedMSC

stransplant

andMSC

sinfusion

Alginateg

elprotectsMSC

sfrom

immun

eattack

andcontrolsGFs

release

Regeneratio

nof

heartscara

ndmuscle


[5657]

Alopecia

Agedise

ase

andmedicine

use

Transplantationof

GAG

-coatedDPC

s

GAG

coatingmim

icsE

CMmicroenvironm

entprom

otingDPC

sregeneratio

n

Regeneratio

nof

hairfollicle

fortreatment

ofalop

ecia

[58]

UCS

Cs

Con

genitalh

eart

defects

Develo

pmental

errors

Transplantationof

fibrin

coaxed

AFS

CsAd

ditio

nof

VEF

Gto

PEGcoaxed

AFS

Csprom

otes

organo

genesis

Regeneratio

nof

tissuer

epairfor

treatmento

fheartdefects

[5960]

Diabetes

Lifesty

leand

genetic

factors

WJ-SC

stransplantation

andintravenou

sinjection

WJ-factorsamp


sinto120573-cells

decreasin

gIL6ampIL1120573

Improvem

entinfunctio


totre

atmento

fdiabetes

[7961ndash63]

SLE

Autoim

mun

ityIntravenou

sinfusionof

WJ-SC

sWJ-SC

sdecreaseS

LEDAIamp

BILA

G

reinfusio

nprotectsfro

mdiseaser

elapse

Improvem

entinrenalfun

ctions

ampsto

ppingdegeneratio

nof

tissues

[64]

LSDamp

neurod

egenerative

diseases

Geneticstumor

ageandlife

style

Allo

genicU

CSCs

cells

andbiom

aterialcoaxed

UCS

Csorgano

ids

Organoids

consisted

ofneurob

lasts

(GFA

P+N

estin+

and

Ki67+

)ampSC

s(O

CT4+SOC2+

)UCS

Csrecoverfrom

MSE

deficiencyandim

provec

ognitio

n

Treatm

ento

fKrabb

ersquosdiseasehu

rler

synd

romeMLD

TSD

ALD

ADA

LS

SCISC

ITB

IParkinsonsstr

okeandso

forth

[65ndash67]

Cartilage

and

tend

oninjurie

sAc

cident

Transplantationof

UCB

-SCs

UCB

-SCs

-HA

gel

HAgelfactorsprom

oter

egenerationof

hyalinec

artilageamp

tend

onsinwks

time

Recovery

from

tend

onsa

ndcartilage

injurie

s[6869]

Hod

gkinrsquos

lymph

oma

Geneticand

environm

ental

Transplantationof

UCS

CsSecond

dose

infectionof

allogenic

UCS

Csim

proves

patie

ntslife

by30

Treatm

ento

fHod

gkinrsquoslymph

omaa

ndotherc

ancers

[10]

Periton

ealfi

brosis

Long

term

renal

dialysisand

fibrosis

WJ-SC

stransplantation

byIP

injection

WJ-SC

sprevent

programmed

cells

death

andperiton

ealw

allthickness

Effectiv

eintre

atmento

fencapsulatin

gperiton

ealfi

brosis

[70]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

BMSC

s

Anaem

iaand

bloo

dcancer

Injurygenetics

autoim

mun

ityTw

o-ste

pinfusio

nof

lymph

oidandmyeloid

Haploidentic

alBM

SCsc

anreconstruct

immun

ityw

hich

ismajor

processfor

minority

Treatm

ento

faplastic

anaemiaamp

haem


[71]

AID

SHIV

1infectio

nTransplantationof

HIV

1resistant

CD4+

cells

Anti-H

IV1C

D4+

cells

expressH

IV1

anti-RN

Aw

hich

restric

tHIV

infection

Treatm

ento

fAID

Sas

analternativeo

fantiretroviral

[7273]

Bloo

dclo

tting

disorders

Lack

ofplatele

tsTransplantationof

megakaryocyte

organo

ids

GFs

insilkspon

gem

icrotubu

le3D

scaffolds

mim

icbo

nemarrow

Therapeutic

sofb

urns

andbloo

dclo

tting

diseases

[7475]

Neurodegenerativ

ediseases

Accidentsage

traumaand

stroke

Focaltransplanto

fBM

SCsw

ithLA

LA+

BMSC

sind

ucen

eovascularisa

tion

thatdirectsm

icrogliaforc

olon

ization

Treatm

ento

fneuronald

amaged

isorders

andcogn

itive

resto

ratio

n[76]

Orodental

deform

ities

Traumadisease

andbirthdefects

Bone

marrowderiv

edste

mampprogenito

r(TRC

)

CD14+

ampCD

90+


jawbo

neregeneratio

nRe

generatio

nof

defectsinoralbo

neskin

andgum

[77]

Diaph

ragm

abno

rmalities

Accidentsamp

birthdefects

Implantatio

nof

decellu

lariz

eddiaphragm

BMSC

sniche

perfused

hemidiaph

ragm

hassim

ilarm

yography

ampspiro

metry

Replacem

enttherapy

bydo

nord

erived

niched

diaphragm

[8]

iPSC

s

Eyed

efects

Agegenetics

andbirthdefects

iPSC

sderived

NPC

stransplantation

NPC

sform

5-6layersof

photoreceptor

nucle

iresto

ringvisualacuity

Treatm

ento

fARM

Dandother

age-related

eyed

efects

[78ndash80]

Neurodegenerativ

edisorders

Accidentsage

traumaand

stroke

iGABA

-INsa

ndcortical

spheroid

transplantation

(iGABA

-INs)secreteG

ABA

FOX1G

causeA

SDsph

eroidmim

icstobrain

ASD

Alzh

eimersseizerand

obstinate

epilepsiestreatment

[81ndash84]

Liveramp

lung

diseases

A1A

Ddeficiency

Transplantationof

A1A

Dmutationcorrected

iPSC

s

A1A

Disencodedby

SERP

INA1inliver


Treatm

ento

fCOPD

causinglung

sand

liver

degeneratio

n[85]

Diabetes

Lifesty

leand

genetic

factors

iPSC


transplantation

Skin


ase

throug

hcD

EampcPFrequ

iresG

PsTreatm

ento

fT1D

MandT2

DM

and

insulin

prod

uctio

n[86]

Lung

degeneratio

nTu

berculosis

cancerand

fibrosis

Biom

aterialcoaxed

iPSC

stransplantatio

nMiniature

iPSC

slun

gresembles

airw

ays

andalveolimod

eldrug

testing

Regeneratio

nof

lung

tissue

[87]

SIDsa

ndAID

SAgegenetic

factorsand

infection

Transplantationof

Oct4

andNanog

corrected

iPSC

s

CRISPE

R-Ca

s9generateiPSC

sinsin

gle

stepiPSC

s-M120601resistsHIV

1Im

mun

otherapy

ofSIDsHIV

1andother

immun

edise

ases

[808889]



Diabetic treatment



Differentiation

COCO

Cone cells

ARMDtreatment


Fibrin embedding


RGC



Pacemakercells


IVG


Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells







Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


ble1Ap

plicationof

stem

cells

inregenerativ

emedicineste

mcells

(ESC

sTS

PSCs

MSC

sUCS

CsB

MSC

sandiPSC

s)have

diverseapplications

intissueregeneratio

nanddisease

therapeutic

s

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

ESCs

Spinalcord

injurie

sInfection

cancerand

accidents

ESCs

transplantationto

injury

site

ESCs

andsecreted

vasculogenicand

neurogenicfactor

supp

orttissue

homing

Regeneratio

nof

spinaltissuea

ndim

proved

balancea

ndsensation

[15]

ARM

Dand

glaucoma

Macular

cones

degeneratio

n

ESCs

-derived

conesa

ndRG

Cstransplantationto

eye

COCO

(activatingTG

F-120573B

MPand

Wnt)amp

BRN3(kno

ck-in

byCR

ISPE

R-Ca

s9)m

akeE

SCsb

ecom

econesa

ndRG

Csform

cells

sheetamp

neuron

alconn

ectio

n

Recovery

from

ARM

Dandmacular

defectsamp

resto

ratio

nof

visio

n[1617]

Cardiovascular

disease

Diabetesdrugs

genetic

factor

andlifes

tyle

ESCs

-derived

CMsamp

biom

aterialcoaxedES

Cs

Cardiomyocytese

xpressGCa

MP3


ox3

differentiatesE

SCsintoSA

NPC

s

Supp

resses

heartarrhythmiasCM

sele

ctroph

ysiologically

integratetoheart

aspacemaker

[181928]

Liverinjuries

Toxinsdrugs

genetic

factors

andinfection

Transplantationof

ESCs

-derived

hepatocytes

ESCs

-hepatocytec

onversionismarked

with

expressio

nof

Cytp450PX

RCY

PA4amp

29H

NF4

-120572and

UGTA

1cells

intransplant

repo

pulateinjured

liver

tissue

Regeneratio

nof

liver

tissuec

anbe

used

asmod

elforscreening

ofdrugs

[202324]

Diabetes

Lifesty

leheart

defectsand

genetic

s

Transplantationof

ESCs

-derived

PPCs

Progenito

rs(C

D24+

CD49+

ampCD

133+)


secreteinsulin

andexpressP

DX1G

CKand

GLU

T2

Improvem


esity

canbe

used

fortreatmento

fT1D

Mand

T2DM

[2526]

Oste

oarthritis

Whencartilage

tissuew

ears

away

Transplantationof

chon

drocytes

organo

ids

Chon

drocytes

(SOX9+

ampcollagen-II+

)form

cells

aggregateamp

remainactiv

efor

12wks


Regeneratio

nof

cartilage

tissuec

anbe

used

fortreatmento

finjuriesfaced

byathletes

[27]

TSPS

Cs

Diabetes

Lifesty

leand

genetic

factors

Transplantationof

SCs

deriv

edPP

Csorgano

idPP

Csneed

niches

uppo

rted

activ

eFGFamp

Notch

signalling

tobecome120573

-cell

PPCs


treatT1DM

ampT2

DM

[252930]

Neurodental

prob

lems

Accidentsage

andgenetic

factors

Transplantationof

DSP

SCsa

sneurons

Neurons

expressn

estin

GFA

P120573III-tubu

linand

L-type

Ca2+

channels


treatmento

fneurod

entalabn

ormalities

[3132]

Acou

sticp

roblem

sAgenoise

drugsand

infection

IESC

sIESC

s-deriv

edhaircells


shutsN

otch

by120573-catenin

ampAtoh

1inlrg

5+IESC

stobe

haircells


resto

ratio

nof

acou

sticfunctio

ns[3435]

Intestinal

degeneratio

n

Geneticfactors

andfood

borne

infections

IPCs

deriv

edcrypt-v

illi

organo

idtransplantation

M120601m

yofib

roblasts

andbacteriasig

nals

IPCs

tobe

crypt-v

illiorganoidtissue

Regeneratio

nof

gobletmucosac

antre

atintestinaldefects

[36ndash

38]

Cornealdiseases

Burnsgenetic

sand

inflammation

LPSC

stransplantatio

nto

cornealtissue

LPSC

sintransplant

markedby

ABC

B5differentiateinto

maturec

ornea

Regeneratio

nof

cornealtissue

might

treat

multip

leeyed

isease

[3940

]

Muscular

deform

ities

Infection

drugs

and

autoim

mun

ity

Transplantationof

PEG

fibrin

ogen

coaxed

MABs

PDGFfro

mMABs

attractvasculogenic

andneurogeniccells

totransplant

site

Muscle

fibril

regeneratio

nskeletal

muscle

defectstreatment

[4142]

Eyed

iseaseamp

retin

opathy

Toxinsburns

andgenetic

factors

AdSC

sintravitre

altransplantation

AdSC

sfrom

healthydo

norp

rodu

cehigh

ervasoprotectiv

efactors

Resto

ratio

nof

vascularisa

tion

diabetic

retin

opathy

treatment

[4445]

Cardiac

dysfu

nctio

ns

Agegenetic

factorsand

toxins

Syste

micinfusio

nof

CA-AdS

Csmyocardium

CA-AdS

Csto

epith

elium

differentiatio

nares

uperiortoAd

SCs

Regeneratio

nof

ischemicmyocardium

[4748]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

MSC

s

Bladder

deform

ities

Cystitiscancer

andinfection

Transplantationof

BD-M

SCstobladder

BDMSC

s(CD

105+C

D73+

CD34minus

and

CD45minus

)with



mdifferent

originsM

SCs

[5051]

Dentalproblem

sInfection

cancer

ageand

accidents

Transplantso

fEMSC

s+DSC

sbiopo

lymer

tissue

EMSC

-DSC

sand


biop

olym

ergive

risetomatureteeth

units

Regeneratio

nof

oraltissuea

ndapplicationin

perio

dontics

[3152]

Bone

degeneratio

nInjurie

sand

tumor

autoim

mun

ity

CoaxedMSC

stransplant

ampMSC

sinfusion

Actin

mod

ellin

gby

cytochalasin-D

transfo

rmsM

SCsintoosteob

lasts

Regeneratio

nof

bonesredu

ctionin

injury

pain

[53ndash55]

Muscle

degeneratio

nGeneticfactors

andworkstr

ess

CoaxedMSC

stransplant

andMSC

sinfusion

Alginateg

elprotectsMSC

sfrom

immun

eattack

andcontrolsGFs

release

Regeneratio

nof

heartscara

ndmuscle


[5657]

Alopecia

Agedise

ase

andmedicine

use

Transplantationof

GAG

-coatedDPC

s

GAG

coatingmim

icsE

CMmicroenvironm

entprom

otingDPC

sregeneratio

n

Regeneratio

nof

hairfollicle

fortreatment

ofalop

ecia

[58]

UCS

Cs

Con

genitalh

eart

defects

Develo

pmental

errors

Transplantationof

fibrin

coaxed

AFS

CsAd

ditio

nof

VEF

Gto

PEGcoaxed

AFS

Csprom

otes

organo

genesis

Regeneratio

nof

tissuer

epairfor

treatmento

fheartdefects

[5960]

Diabetes

Lifesty

leand

genetic

factors

WJ-SC

stransplantation

andintravenou

sinjection

WJ-factorsamp


sinto120573-cells

decreasin

gIL6ampIL1120573

Improvem

entinfunctio


totre

atmento

fdiabetes

[7961ndash63]

SLE

Autoim

mun

ityIntravenou

sinfusionof

WJ-SC

sWJ-SC

sdecreaseS

LEDAIamp

BILA

G

reinfusio

nprotectsfro

mdiseaser

elapse

Improvem

entinrenalfun

ctions

ampsto

ppingdegeneratio

nof

tissues

[64]

LSDamp

neurod

egenerative

diseases

Geneticstumor

ageandlife

style

Allo

genicU

CSCs

cells

andbiom

aterialcoaxed

UCS

Csorgano

ids

Organoids

consisted

ofneurob

lasts

(GFA

P+N

estin+

and

Ki67+

)ampSC

s(O

CT4+SOC2+

)UCS

Csrecoverfrom

MSE

deficiencyandim

provec

ognitio

n

Treatm

ento

fKrabb

ersquosdiseasehu

rler

synd

romeMLD

TSD

ALD

ADA

LS

SCISC

ITB

IParkinsonsstr

okeandso

forth

[65ndash67]

Cartilage

and

tend

oninjurie

sAc

cident

Transplantationof

UCB

-SCs

UCB

-SCs

-HA

gel

HAgelfactorsprom

oter

egenerationof

hyalinec

artilageamp

tend

onsinwks

time

Recovery

from

tend

onsa

ndcartilage

injurie

s[6869]

Hod

gkinrsquos

lymph

oma

Geneticand

environm

ental

Transplantationof

UCS

CsSecond

dose

infectionof

allogenic

UCS

Csim

proves

patie

ntslife

by30

Treatm

ento

fHod

gkinrsquoslymph

omaa

ndotherc

ancers

[10]

Periton

ealfi

brosis

Long

term

renal

dialysisand

fibrosis

WJ-SC

stransplantation

byIP

injection

WJ-SC

sprevent

programmed

cells

death

andperiton

ealw

allthickness

Effectiv

eintre

atmento

fencapsulatin

gperiton

ealfi

brosis

[70]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

BMSC

s

Anaem

iaand

bloo

dcancer

Injurygenetics

autoim

mun

ityTw

o-ste

pinfusio

nof

lymph

oidandmyeloid

Haploidentic

alBM

SCsc

anreconstruct

immun

ityw

hich

ismajor

processfor

minority

Treatm

ento

faplastic

anaemiaamp

haem


[71]

AID

SHIV

1infectio

nTransplantationof

HIV

1resistant

CD4+

cells

Anti-H

IV1C

D4+

cells

expressH

IV1

anti-RN

Aw

hich

restric

tHIV

infection

Treatm

ento

fAID

Sas

analternativeo

fantiretroviral

[7273]

Bloo

dclo

tting

disorders

Lack

ofplatele

tsTransplantationof

megakaryocyte

organo

ids

GFs

insilkspon

gem

icrotubu

le3D

scaffolds

mim

icbo

nemarrow

Therapeutic

sofb

urns

andbloo

dclo

tting

diseases

[7475]

Neurodegenerativ

ediseases

Accidentsage

traumaand

stroke

Focaltransplanto

fBM

SCsw

ithLA

LA+

BMSC

sind

ucen

eovascularisa

tion

thatdirectsm

icrogliaforc

olon

ization

Treatm

ento

fneuronald

amaged

isorders

andcogn

itive

resto

ratio

n[76]

Orodental

deform

ities

Traumadisease

andbirthdefects

Bone

marrowderiv

edste

mampprogenito

r(TRC

)

CD14+

ampCD

90+


jawbo

neregeneratio

nRe

generatio

nof

defectsinoralbo

neskin

andgum

[77]

Diaph

ragm

abno

rmalities

Accidentsamp

birthdefects

Implantatio

nof

decellu

lariz

eddiaphragm

BMSC

sniche

perfused

hemidiaph

ragm

hassim

ilarm

yography

ampspiro

metry

Replacem

enttherapy

bydo

nord

erived

niched

diaphragm

[8]

iPSC

s

Eyed

efects

Agegenetics

andbirthdefects

iPSC

sderived

NPC

stransplantation

NPC

sform

5-6layersof

photoreceptor

nucle

iresto

ringvisualacuity

Treatm

ento

fARM

Dandother

age-related

eyed

efects

[78ndash80]

Neurodegenerativ

edisorders

Accidentsage

traumaand

stroke

iGABA

-INsa

ndcortical

spheroid

transplantation

(iGABA

-INs)secreteG

ABA

FOX1G

causeA

SDsph

eroidmim

icstobrain

ASD

Alzh

eimersseizerand

obstinate

epilepsiestreatment

[81ndash84]

Liveramp

lung

diseases

A1A

Ddeficiency

Transplantationof

A1A

Dmutationcorrected

iPSC

s

A1A

Disencodedby

SERP

INA1inliver


Treatm

ento

fCOPD

causinglung

sand

liver

degeneratio

n[85]

Diabetes

Lifesty

leand

genetic

factors

iPSC


transplantation

Skin


ase

throug

hcD

EampcPFrequ

iresG

PsTreatm

ento

fT1D

MandT2

DM

and

insulin

prod

uctio

n[86]

Lung

degeneratio

nTu

berculosis

cancerand

fibrosis

Biom

aterialcoaxed

iPSC

stransplantatio

nMiniature

iPSC

slun

gresembles

airw

ays

andalveolimod

eldrug

testing

Regeneratio

nof

lung

tissue

[87]

SIDsa

ndAID

SAgegenetic

factorsand

infection

Transplantationof

Oct4

andNanog

corrected

iPSC

s

CRISPE

R-Ca

s9generateiPSC

sinsin

gle

stepiPSC

s-M120601resistsHIV

1Im

mun

otherapy

ofSIDsHIV

1andother

immun

edise

ases

[808889]



Diabetic treatment



Differentiation

COCO

Cone cells

ARMDtreatment


Fibrin embedding


RGC



Pacemakercells


IVG


Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells







Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

MSC

s

Bladder

deform

ities

Cystitiscancer

andinfection

Transplantationof

BD-M

SCstobladder

BDMSC

s(CD

105+C

D73+

CD34minus

and

CD45minus

)with



mdifferent

originsM

SCs

[5051]

Dentalproblem

sInfection

cancer

ageand

accidents

Transplantso

fEMSC

s+DSC

sbiopo

lymer

tissue

EMSC

-DSC

sand


biop

olym

ergive

risetomatureteeth

units

Regeneratio

nof

oraltissuea

ndapplicationin

perio

dontics

[3152]

Bone

degeneratio

nInjurie

sand

tumor

autoim

mun

ity

CoaxedMSC

stransplant

ampMSC

sinfusion

Actin

mod

ellin

gby

cytochalasin-D

transfo

rmsM

SCsintoosteob

lasts

Regeneratio

nof

bonesredu

ctionin

injury

pain

[53ndash55]

Muscle

degeneratio

nGeneticfactors

andworkstr

ess

CoaxedMSC

stransplant

andMSC

sinfusion

Alginateg

elprotectsMSC

sfrom

immun

eattack

andcontrolsGFs

release

Regeneratio

nof

heartscara

ndmuscle


[5657]

Alopecia

Agedise

ase

andmedicine

use

Transplantationof

GAG

-coatedDPC

s

GAG

coatingmim

icsE

CMmicroenvironm

entprom

otingDPC

sregeneratio

n

Regeneratio

nof

hairfollicle

fortreatment

ofalop

ecia

[58]

UCS

Cs

Con

genitalh

eart

defects

Develo

pmental

errors

Transplantationof

fibrin

coaxed

AFS

CsAd

ditio

nof

VEF

Gto

PEGcoaxed

AFS

Csprom

otes

organo

genesis

Regeneratio

nof

tissuer

epairfor

treatmento

fheartdefects

[5960]

Diabetes

Lifesty

leand

genetic

factors

WJ-SC

stransplantation

andintravenou

sinjection

WJ-factorsamp


sinto120573-cells

decreasin

gIL6ampIL1120573

Improvem

entinfunctio


totre

atmento

fdiabetes

[7961ndash63]

SLE

Autoim

mun

ityIntravenou

sinfusionof

WJ-SC

sWJ-SC

sdecreaseS

LEDAIamp

BILA

G

reinfusio

nprotectsfro

mdiseaser

elapse

Improvem

entinrenalfun

ctions

ampsto

ppingdegeneratio

nof

tissues

[64]

LSDamp

neurod

egenerative

diseases

Geneticstumor

ageandlife

style

Allo

genicU

CSCs

cells

andbiom

aterialcoaxed

UCS

Csorgano

ids

Organoids

consisted

ofneurob

lasts

(GFA

P+N

estin+

and

Ki67+

)ampSC

s(O

CT4+SOC2+

)UCS

Csrecoverfrom

MSE

deficiencyandim

provec

ognitio

n

Treatm

ento

fKrabb

ersquosdiseasehu

rler

synd

romeMLD

TSD

ALD

ADA

LS

SCISC

ITB

IParkinsonsstr

okeandso

forth

[65ndash67]

Cartilage

and

tend

oninjurie

sAc

cident

Transplantationof

UCB

-SCs

UCB

-SCs

-HA

gel

HAgelfactorsprom

oter

egenerationof

hyalinec

artilageamp

tend

onsinwks

time

Recovery

from

tend

onsa

ndcartilage

injurie

s[6869]

Hod

gkinrsquos

lymph

oma

Geneticand

environm

ental

Transplantationof

UCS

CsSecond

dose

infectionof

allogenic

UCS

Csim

proves

patie

ntslife

by30

Treatm

ento

fHod

gkinrsquoslymph

omaa

ndotherc

ancers

[10]

Periton

ealfi

brosis

Long

term

renal

dialysisand

fibrosis

WJ-SC

stransplantation

byIP

injection

WJ-SC

sprevent

programmed

cells

death

andperiton

ealw

allthickness

Effectiv

eintre

atmento

fencapsulatin

gperiton

ealfi

brosis

[70]


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

BMSC

s

Anaem

iaand

bloo

dcancer

Injurygenetics

autoim

mun

ityTw

o-ste

pinfusio

nof

lymph

oidandmyeloid

Haploidentic

alBM

SCsc

anreconstruct

immun

ityw

hich

ismajor

processfor

minority

Treatm

ento

faplastic

anaemiaamp

haem


[71]

AID

SHIV

1infectio

nTransplantationof

HIV

1resistant

CD4+

cells

Anti-H

IV1C

D4+

cells

expressH

IV1

anti-RN

Aw

hich

restric

tHIV

infection

Treatm

ento

fAID

Sas

analternativeo

fantiretroviral

[7273]

Bloo

dclo

tting

disorders

Lack

ofplatele

tsTransplantationof

megakaryocyte

organo

ids

GFs

insilkspon

gem

icrotubu

le3D

scaffolds

mim

icbo

nemarrow

Therapeutic

sofb

urns

andbloo

dclo

tting

diseases

[7475]

Neurodegenerativ

ediseases

Accidentsage

traumaand

stroke

Focaltransplanto

fBM

SCsw

ithLA

LA+

BMSC

sind

ucen

eovascularisa

tion

thatdirectsm

icrogliaforc

olon

ization

Treatm

ento

fneuronald

amaged

isorders

andcogn

itive

resto

ratio

n[76]

Orodental

deform

ities

Traumadisease

andbirthdefects

Bone

marrowderiv

edste

mampprogenito

r(TRC

)

CD14+

ampCD

90+


jawbo

neregeneratio

nRe

generatio

nof

defectsinoralbo

neskin

andgum

[77]

Diaph

ragm

abno

rmalities

Accidentsamp

birthdefects

Implantatio

nof

decellu

lariz

eddiaphragm

BMSC

sniche

perfused

hemidiaph

ragm

hassim

ilarm

yography

ampspiro

metry

Replacem

enttherapy

bydo

nord

erived

niched

diaphragm

[8]

iPSC

s

Eyed

efects

Agegenetics

andbirthdefects

iPSC

sderived

NPC

stransplantation

NPC

sform

5-6layersof

photoreceptor

nucle

iresto

ringvisualacuity

Treatm

ento

fARM

Dandother

age-related

eyed

efects

[78ndash80]

Neurodegenerativ

edisorders

Accidentsage

traumaand

stroke

iGABA

-INsa

ndcortical

spheroid

transplantation

(iGABA

-INs)secreteG

ABA

FOX1G

causeA

SDsph

eroidmim

icstobrain

ASD

Alzh

eimersseizerand

obstinate

epilepsiestreatment

[81ndash84]

Liveramp

lung

diseases

A1A

Ddeficiency

Transplantationof

A1A

Dmutationcorrected

iPSC

s

A1A

Disencodedby

SERP

INA1inliver


Treatm

ento

fCOPD

causinglung

sand

liver

degeneratio

n[85]

Diabetes

Lifesty

leand

genetic

factors

iPSC


transplantation

Skin


ase

throug

hcD

EampcPFrequ

iresG

PsTreatm

ento

fT1D

MandT2

DM

and

insulin

prod

uctio

n[86]

Lung

degeneratio

nTu

berculosis

cancerand

fibrosis

Biom

aterialcoaxed

iPSC

stransplantatio

nMiniature

iPSC

slun

gresembles

airw

ays

andalveolimod

eldrug

testing

Regeneratio

nof

lung

tissue

[87]

SIDsa

ndAID

SAgegenetic

factorsand

infection

Transplantationof

Oct4

andNanog

corrected

iPSC

s

CRISPE

R-Ca

s9generateiPSC

sinsin

gle

stepiPSC

s-M120601resistsHIV

1Im

mun

otherapy

ofSIDsHIV

1andother

immun

edise

ases

[808889]



Diabetic treatment



Differentiation

COCO

Cone cells

ARMDtreatment


Fibrin embedding


RGC



Pacemakercells


IVG


Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells







Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table1Con

tinued

SCs

Dise

ase

Factorsc

ausin

gdisease

Mod

eofstem

cells

application

Physiologicaland

mechanisticaspectso

fste

mcells

therapeutics

Improvem

entsin

diseases

ignaturesamp

future

use

References

BMSC

s

Anaem

iaand

bloo

dcancer

Injurygenetics

autoim

mun

ityTw

o-ste

pinfusio

nof

lymph

oidandmyeloid

Haploidentic

alBM

SCsc

anreconstruct

immun

ityw

hich

ismajor

processfor

minority

Treatm

ento

faplastic

anaemiaamp

haem


[71]

AID

SHIV

1infectio

nTransplantationof

HIV

1resistant

CD4+

cells

Anti-H

IV1C

D4+

cells

expressH

IV1

anti-RN

Aw

hich

restric

tHIV

infection

Treatm

ento

fAID

Sas

analternativeo

fantiretroviral

[7273]

Bloo

dclo

tting

disorders

Lack

ofplatele

tsTransplantationof

megakaryocyte

organo

ids

GFs

insilkspon

gem

icrotubu

le3D

scaffolds

mim

icbo

nemarrow

Therapeutic

sofb

urns

andbloo

dclo

tting

diseases

[7475]

Neurodegenerativ

ediseases

Accidentsage

traumaand

stroke

Focaltransplanto

fBM

SCsw

ithLA

LA+

BMSC

sind

ucen

eovascularisa

tion

thatdirectsm

icrogliaforc

olon

ization

Treatm

ento

fneuronald

amaged

isorders

andcogn

itive

resto

ratio

n[76]

Orodental

deform

ities

Traumadisease

andbirthdefects

Bone

marrowderiv

edste

mampprogenito

r(TRC

)

CD14+

ampCD

90+


jawbo

neregeneratio

nRe

generatio

nof

defectsinoralbo

neskin

andgum

[77]

Diaph

ragm

abno

rmalities

Accidentsamp

birthdefects

Implantatio

nof

decellu

lariz

eddiaphragm

BMSC

sniche

perfused

hemidiaph

ragm

hassim

ilarm

yography

ampspiro

metry

Replacem

enttherapy

bydo

nord

erived

niched

diaphragm

[8]

iPSC

s

Eyed

efects

Agegenetics

andbirthdefects

iPSC

sderived

NPC

stransplantation

NPC

sform

5-6layersof

photoreceptor

nucle

iresto

ringvisualacuity

Treatm

ento

fARM

Dandother

age-related

eyed

efects

[78ndash80]

Neurodegenerativ

edisorders

Accidentsage

traumaand

stroke

iGABA

-INsa

ndcortical

spheroid

transplantation

(iGABA

-INs)secreteG

ABA

FOX1G

causeA

SDsph

eroidmim

icstobrain

ASD

Alzh

eimersseizerand

obstinate

epilepsiestreatment

[81ndash84]

Liveramp

lung

diseases

A1A

Ddeficiency

Transplantationof

A1A

Dmutationcorrected

iPSC

s

A1A

Disencodedby

SERP

INA1inliver


Treatm

ento

fCOPD

causinglung

sand

liver

degeneratio

n[85]

Diabetes

Lifesty

leand

genetic

factors

iPSC


transplantation

Skin


ase

throug

hcD

EampcPFrequ

iresG

PsTreatm

ento

fT1D

MandT2

DM

and

insulin

prod

uctio

n[86]

Lung

degeneratio

nTu

berculosis

cancerand

fibrosis

Biom

aterialcoaxed

iPSC

stransplantatio

nMiniature

iPSC

slun

gresembles

airw

ays

andalveolimod

eldrug

testing

Regeneratio

nof

lung

tissue

[87]

SIDsa

ndAID

SAgegenetic

factorsand

infection

Transplantationof

Oct4

andNanog

corrected

iPSC

s

CRISPE

R-Ca

s9generateiPSC

sinsin

gle

stepiPSC

s-M120601resistsHIV

1Im

mun

otherapy

ofSIDsHIV

1andother

immun

edise

ases

[808889]



Diabetic treatment



Differentiation

COCO

Cone cells

ARMDtreatment


Fibrin embedding


RGC



Pacemakercells


IVG


Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells







Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Diabetic treatment



Differentiation

COCO

Cone cells

ARMDtreatment


Fibrin embedding


RGC



Pacemakercells


IVG


Ther

apeu

tic ap

plic

atio

ns

Ther

apeu

tic ap

plic

atio

ns

K2 + LA

120573-cells







Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Ther

apeu

ticap

plic

atio

ns









Auditory hair cells


SSCs


Epithelium

Skin

Prostate

Intestine


Limbal stem cells


Corneal occupancy


Pancreatic organoid


3Dculture

Insulin therapy


Intestinal tissue


3D culture

Ther

apeu

ticap

plic

atio

ns


Neurogenesis

Serotonin neurons

AdSCs



Infusion toMI heart

SKPs

VSMCs




+Mesenchyma of







MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




MSCs

DPCS-LBL-GAG


Hair reconstitution



of bladder tissue








Muscle regeneration

coculture


coating + FGF2


AD-MSCs +M120601





Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Cord cellsbanking

Umbilical arteries

Whartonrsquos Jelly









Infusion of UCSCs




disease






tendon tear-site



neutropenia




term dialysis

2x tra

nsplantat

ion

UCB-MSCs + HA









Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Diaphragm scaffold



Appl

icat

ions

Redmarrow





HIV1 resistant

BMSCs BMSCs

Brain tissue

injuries treatment

Megakaryocytes

Monocytes

wound healing


Craniofacial tissue


BMSCs


function in mice



of liver functions

(CD4+) HSC and PSC

CD4+ cells



+LA+HIV1 antisense







iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



iPSCs


Trophoblastic cells

Kidney organoid

Photoreceptor cells

Healthypatient


Heart valve cells

Skin cells





tissue

Healing ofbrain

defects



Pacemakerimpairment

recovery



tissue




disorders


Appl

icat

ions

Appl

icat

ions


+

120573-cells







Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Skin biopsies


iPSCs


In vitromaturation

In vivo maturation










































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


































Abbreviations








Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology







Competing Interests


Acknowledgments


References












































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

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