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8/17/2019 Cord Blood SC-A0915 RogerLaham CORDBLO Wed

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Cord Blood: Between ES andAdult Stem Cells?

CRT 2006

Roger J. Laham, MDRoger J. Laham, MDDirector, Angiogenesis Research Center Director, Angiogenesis Research Center

Assistant Director, Interventional CardiologyAssistant Director, Interventional Cardiology

Director, Basic Angioplasty ResearchDirector, Basic Angioplasty ResearchAssociate Professor of MedicineAssociate Professor of MedicineBIDMC!arvard Medical "choolBIDMC!arvard Medical "chool


2/21

Conflict of Interest StatementConflict of Interest Statement

Roger Laham, MD

I have no real or apparent conflicts of interest to report.


3/21

Lost in #ranslation$$

% Despite decades of research and !ears ofclinical trials" therapeutic an#io#enesis$

m!ocardial re#eneration remains elusi%e

% Bench" preclinical" and earl! clinical resultsare incredi&le" onl! to crash in later sta#es

of de%elopment

% '('s" )E('s as proteins or #enes" s*eletalm!o&lasts" &one marrow cells" +and ,stem

cell-

Kenneth Chien


4/21

&hy the fail'res and disappointments$

% An#io#enesis$m!o#enesis are comple. processesand multiple steps are needed for functionall!

si#nificant an#io#enesis

% Tar#et population is older" ha%e endotheliald!sfunction" h!percholesterolenemia" and scarred

m!ocardium" /uite different from commonl! used

animal models 1u%enile" normocholesterolenemic"

normal endothelial funtion

% Deli%er!" a#ent handlin#" +% 3utcome measures


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(lder Age

4 6 25C

7

0hours

8on97

)E('

2:s

4 6 25C

7

0hours

8on97

)E('

2:s


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Ad'lt !yperChol Animals


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"o )hy Cord Blood$$

% Adult stem cells ma! ha%e limitedtransdifferentiation potential and ma! &e

limited &! a#in# process

% Em&r!onic stem cells while trul! promisin#carr! an ethical 8euse

% Cord &lood deri%ed stem cells ma! &e morecapa&le of transdifferentiation than adult

cells and ma! carr! less sti#ma???


8/21

*ot a ne) idea, Crisa, Blood +

% As compared )ith ad'lt -one marro), cord -lood

progenitor cells have -een sho)n to have a higher proliferative and selfrene)al potential

% BM reconstit'tion )ith cord -lood led to engraftment ofcord -loodderived progenitors of the endothelial lineage,)hich )ere recr'ited to form ne) -lood vessels e/tending

from the thymic implant into the s'rro'nding mo'se tiss'e


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Cord -lood derived progenitor cells% 0m-ilical cord -lood contains circ'lating stemprogenitor cells

e1'al or e/ceeding -one marro) and greatly s'rpassing ad'lt

peripheral -lood% "tem cells from cord -lood e/pand longer in c'lt're, prod'ce larger

hematopoietic clones in vitro, and have longer telomeres

% Cord -lood also contains mesenchymal progenitor cells capa-le of

differentiating into marro) stroma, -one, and m'scle, and theimmat'rity of neonatal cells compared )ith ad'lt cells doestranslate into greater cell plasticity )ith a com-ination of f'sionand transdifferentiation

% $$$$Imm'nogenicity

Le Ricousse-Roussanne, Cardiovascular Res 2004 Pesce, Circ Res 2003


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2/perimental Design

34 "CID*(D mice 34 56B mice

LAD Ligation MI model

"ham In7ection Cord -lood Monon'clear

In7ection 8+/+49:

"acrifice at 9 and +; days

!emodynamics, ##C staining, Imm'nohistochemistry 8!*A and!LA+ antigen Colocali5, -5>5, #>5-eta:


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!emodynamics

0

10

20

30

40

50

60

70

80

90

100

AOP LVP LVEDP

m m H g

control

treatment

;


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CD=;? Cord -lood in *(D"CID mo'se MImodel

Control#reatment

0

500

1000

1500

2000

2500

3000

+ dp/dt max - dp/dt max

m m H g / s e c

control

treatment

;


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Cord -lood in mice@ ##C staining

Control #reated

# # C s t a i n i n g A M I

Control #reatment

P4.44


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!istologyCONTROL TR!T"NT

H#

Trichrome


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CD=+ "taining

$%&.&&&'

Treatment Control

C ( ) ' + c e l l s / h p f

Treatment

Control


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&hat are the potential mechanisms

% ;h!sical: 7ncrease wall thic*ness

;re%ention of ne#ati%e remodellin#

'i&rosis with tetherin# of in1ured wall% Biolo#ic: 7nflammation or a#ent induced an#io#enesis

and re%asculariation

Repopulation of dama#ed cells


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Remodelling@

NC MI-C NC-TX MI- TX

TIMP-2

MMP-2

MMP3


18/21

!LA#*I!*A


19/21

Imm'notolerance

% Same results seen in SC7D983D and ')B

and duplicates pre%ious data in rats with noecidence of re1ection at 5 months


20/21

&or in progress

% @ar#e animal model of porcine and umanCord &lood implantation

% CRE9@o. recom&ination to assess the

contri&ution of fusion %s=Transdifferentiation

% Seedin# cord &lood on decellularied matri.and scaffolds to in%esti#ate role of

e.tracellular milieu

% Stud!in# %arious su&populations of cord&lood and cord elements


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Colleag'es Colla-orators

The First Affiliated Hosital of !un

"at-sen

#uifu $u

%niversit& of 'ue(ec

Pierre 6oisine

Incheon, Eorea

"e'ng 0n Lee

Roger Laham Michael -ennett

Jian Li Alicia Maclei

Joanna &yr

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