Mesenchymal stem cell:applications

revision session

PV GuillotLaboratory of Fetal Stem Cell

Therapy

BSc in Reproductive & Developmental Sciences

Learning outcomes the end of the lecture, you should be able to :

1. Define mesenchymal stem cells (MSCs)

2. Illustrate the complexity/variability of MSCs

3. Describe the main features of MSCs

4. Compare & contrast various types of MSCs

5. Illustrate some possible use of MSCs

1. Definition of 1. Definition of mesenchymalmesenchymalstem cells (MSC)stem cells (MSC)

2. The complexity of 2. The complexity of MSCsMSCs

3. The utility of 3. The utility of MSCsMSCs

1. Definition of 1. Definition of mesenchymalmesenchymalstem cells (MSC)stem cells (MSC)

• (1) unspecialized, (2) self renew and (3) can differentiate

• Isolated from tissues (somatic vs embryonic)

• They are non-haemopoiteic

• Can be found in several tissues

• Can be found at various stage of the development

• Multipotent to pluripotent

• Ex: adult bone marrow, fetal liver, cord blood

2. The 2. The complexitycomplexity / variability / variabilityof of MSCsMSCs

• tissue of origin / microenvironment• stage of development• differentiation capacity• accessibility• growth rate• adhesion• telomere length and telomerase activity• migration• engraftment• repair capacity• etc …..

3. The utility of 3. The utility of MSCsMSCs

What do you know ?What do you know ?

What is regenerative medicine?What is regenerative medicine?

What is regenerati ve medicine? The goal of regenerat ive

medicine is to repa ir organs or tissues that are damaged by

disease, aging or trauma, such that function is restored, or at least improved. The term regenerative medicine is often used nowadays

to describe medical treatments and research that use stem cells

(either adult or embryonic) to restore th e function of organs o r

tissues. This can be achieved in different ways; first, by administering stem cells, or specific cells that are derived from stem

cells in the laboratory; or second, by administering drugs that coax

stem cells that are already present in tissues to more efficiently

repair the involved tissue.

transplantation of MSCtransplantation of MSC RationaleRationale

What would you say?What would you say?

•• provide healthy cellsprovide healthy cells

transplantation of MSCtransplantation of MSC RationaleRationale

•• that will survive,that will survive,

•• migrate to various organs,migrate to various organs,•• engraft engraft ……. . •• ………… preferentially at site of injury preferentially at site of injury•• differentiate into specific lineagedifferentiate into specific lineage•• participate to tissue repairparticipate to tissue repair

Prenatal or postnatal cellPrenatal or postnatal celltherapy?therapy?

What do you think?What do you think?

Fetal cell therapyFetal cell therapyIntrauterine transplantationIntrauterine transplantation

of human fetal MSCof human fetal MSC

• delivery before immunecompetence

• give cells beforeirreversible damage

• fetal environment:expansion of endogenous SCcompartment

• stochiometric advantage dueto small size of fetus

GENETIC DISEASEGENETIC DISEASEWITH EARLY ONSETWITH EARLY ONSET

What are the obstacles that must be o vercome before the

potential uses of stem cells in cell therapy will be

realized? Here are just a few of the cha llenges that lie ahead. Firstly, a source of s tem cells must be fo und. The process of

identifying, isolating and growing the right kind of stem cell, for

example a rare cell in the adult tissue, is painstaking. In general,

embryonic and fetal stem cells are believed to b e more versatile than tissue-specific stem cells. Secondly, once stem cells are

identified and isolated, the right conditions must be developed so

that the cells differentiate into the specialized cells required for a

particular therapy. T his too will require a great deal of experimentation. Thirdly, a system that delivers the cells to the

right part of the body must be developed and the cells once there

must be encouraged to i ntegrate and function in concert with the

body's natural cells. Furthermore, just as in organ transplants, the body's immune system must be suppressed to minimize the

immune reaction set off by the transplanted cells.While results from

animal models are promising, the research on stem cells and their

applications to treat various human diseases is still at a preliminary

stage. As w ith any medical treatment, a rigorous research an d testing process must be followed to ensure long-term efficacy and

safety.

Osteogenesis Imperfecta Osteogenesis Imperfecta (OI):(OI):

• Genetic disease: 1/10,000 birth

• Abnormal Col(I) protein

• Bone fragility (fractures: up to 10/year)

• Death

• Prenatal onset

• No cure

ANIMAL MODELANIMAL MODEL

• Multiple fractures• Skeletal difformities• Bone bending• Reduced size•Due to missing proteinalpha 2 collagen type I

………….Intrauterine.Intrauterinetransplantation of fetaltransplantation of fetalMSCMSC……..

HumerusUlna

FemurTibia

OIM+IUT

0

10

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OIM+IUT

OIM

4 8 12 4 8 12

OIMOIM+IUT

Reduction of fracture incidenceReduction of fracture incidence

HUMERUS ULNA FEMUR TIBIAHUMERUS ULNA FEMUR TIBIA

4 8 12 4 8 12 4 8 12 4 8 12

Thicker bonesThicker bones

0.0

0.1

0.2

0.3

1 2 3 4 5

OIM+IUT

OIM

** *

P<0.05

4 8 12 wks

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Fate of donor cellsFate of donor cells Higher engraftment in bonesHigher engraftment in bones

**P<0.01

Fate of donor cellsFate of donor cellsProduction of missing proteinProduction of missing protein

CONCLUSIONSCONCLUSIONS

• stronger• longer

Early Fetal MSCEarly Fetal MSC IUT in IUT in oimoim

BONEBONEFractures, weak, Short, tall GP

Decreased pathologyDecreased pathologyContribute to bone formationContribute to bone formation

Donor cells:Donor cells:

•• migrate and survivemigrate and survive•• engraft broadly engraft broadly•• circulate in blood circulate in blood•• are stored in BM are stored in BM• low engraftmentlow engraftment•• higher in injured tissues higher in injured tissues•• higher at injury site higher at injury site•• produced bone produced bone•• produced missing protein produced missing protein

readingGuillot PV; Cui W; Fisk NM; Polak DJ. (Sep 2007). Stem cell

differentiation and expansion for clinical applications oftissue engineering. J Cell Mol Med. 11:935-944.

Guillot PV; Abass O; Bassett JH; Shefelbine SJ; Bou-Gharios G;Chan J; Kurata H; Williams GR; Polak J; Fisk NM. (01 Feb2008). Intrauterine transplantation of human fetalmesenchymal stem cells from first-trimester blood repairsbone and reduces fractures in osteogenesis imperfectamice. Blood. 111:1717-1725.

Reading complementary