Cord Blood: Between ES and

Adult Stem Cells?

CRT 2006
Roger J. Laham, MD
Director, Angiogenesis Research Center
Assistant Director, Interventional Cardiology
Director, Basic Angioplasty Research
Associate Professor of Medicine
BIDMC/Harvard Medical School

Conflict of Interest Statement

Roger Laham, MD
I have no real or apparent conflicts of interest to report.

Lost in Translation??

Kenneth Chien

Despite decades of research and 11 years of

clinical trials, therapeutic angiogenesis/
myocardial regeneration remains elusive
Bench, preclinical, and early clinical results
are incredible, only to crash in later stages
of development
FGFs, VEGFs as proteins or genes, skeletal
myoblasts, bone marrow cells, and stem
cell

Why the failures and disappointments?

Angiogenesis/myogenesis are complex processes
and multiple steps are needed for functionally
significant angiogenesis
Target population is older, have endothelial
dysfunction, hypercholesterolenemia, and scarred
myocardium, quite different from commonly used
animal models (juvenile, normocholesterolenemic,
normal endothelial funtion)
Delivery, agent handling,
Outcome measures

Older Age

Non-MI
C
1

MI
3

24

(hours)
VEGF
28s

Adult HyperChol Animals

So why Cord Blood??

Adult stem cells may have limited
transdifferentiation potential and may be
limited by aging process
Embryonic stem cells while truly promising
carry an ethical Neuse
Cord blood derived stem cells may be more
capable of transdifferentiation than adult
cells and may carry less stigma???

Not a new idea, Crisa, Blood 1999

As compared with adult bone marrow, cord blood

progenitor cells have been shown to have a higher

proliferative and self-renewal potential
BM reconstitution with cord blood led to engraftment of
cord blood-derived progenitors of the endothelial lineage,
which were recruited to form new blood vessels extending
from the thymic implant into the surrounding mouse tissue

Cord blood derived progenitor cells

Umbilical cord blood contains circulating stem/progenitor cells

equal or exceeding bone marrow and greatly surpassing adult

peripheral blood
Stem cells from cord blood expand longer in culture, produce larger
hematopoietic clones in vitro, and have longer telomeres
Cord blood also contains mesenchymal progenitor cells capable of
differentiating into marrow stroma, bone, and muscle, and the
immaturity of neonatal cells compared with adult cells does
translate into greater cell plasticity with a combination of fusion
and transdifferentiation
????Immunogenicity

Le Ricousse-Roussanne, Cardiovascular Res 2004

Pesce, Circ Res 2003

Experimental Design
20 SCID-NOD mice

20 FVB mice

LAD Ligation MI model

Sham Injection

Cord blood Mononuclear

Injection (1x107)

Sacrifice at 7 and 14 days

Hemodynamics, TTC staining, Immunohistochemistry (HNA and
HLA-1 antigen Colocalization with TnI, CD31, VEGF, bFGF, TGF-beta)

Hemodynamics

100
90

P=0.06

P=0.04

80

mmHg

70
60
50

P=0.14

40
30
20
10
0
AOP

LVP

LVEDP

control
treatment

CD34+ Cord blood in NOD/SCID mouse MI

model
Control

3000

P=0.013

Treatment

P=0.015

mmHg/sec

2500
2000
1500
1000
500
0
+ dp/dt max

- dp/dt max

control
treatment

Cord blood in mice: TTC staining

Control

Treated

TTC staining %MI

P=0.009

Control

Treatment

CONTROL
H&E

Trichrome

Histology

TREATMENT

CD-31 Staining

CD31+ cells/ hpf

P<0.0001

Treatment

Treatment

Control
Control

What are the potential mechanisms

Physical:
Increase wall thickness
Prevention of negative remodelling
Fibrosis with tethering of injured wall

Biologic:
Inflammation or agent induced angiogenesis

and revascularization
Repopulation of damaged cells

Remodelling:
MMP-2

TIMP-2
NC
TX

MI-C

NC-TX MI-

MMP-2

HLA/TNI/HNA

Immuno-tolerance
Same results seen in SCID-NOD and FVB
and duplicates previous data in rats with no
ecidence of rejection at 4 months

Work in progress
Large animal model of porcine and Human
Cord blood implantation
CRE-Lox recombination to assess the
contribution of fusion vs.
Transdifferentiation
Seeding cord blood on decellularized matrix
and scaffolds to investigate role of
extracellular milieu
Studying various subpopulations of cord
blood and cord elements

Colleagues & Collaborators

BI & HMS
Roger Laham
Jian Li
Joanna Wykrzykowska
Audrey Rosinberg
Laurel Donnell-Fink
Jue long Shie
Tanveer Khan
Jianyi Li

Michael bennett
The First Affiliated Hospital of Sun
Alicia Macklei
Yat-sen
Frank Sellke
Shigetoshi Mieno Guifu Wu
University of Quebec
Pierre Voisine
Incheon, Korea
Seung Unk Lee