Appendix M. 
Potential Use Of Cellular Therapy 
For Patients With Heart Disease 
SILVIU ITESCUM.D. 
Departments of Medicine and Surgery, Columbia University, 
New York, NY 
Summary 
Congestive heart failure remains a major public health 
problem, and is frequently the end result of cardiomyocyte apoptosis 
and fibrous replacement after myocardial infarction, a process 
referred to as left ventricular remodelling. Cardiomyocyte s undergo 
terminal differentiation soon after birth, and are generally considered 
to irreversibly withdraw from the cell cycle. In response to ischemic 
insult, adult cardiomyocytes undergo cellular hypertrophy, nuclear 
ploidy, and a high degree of apoptosis. A small number of human 
cardiomyocytes retain the capacity to proliferate and regenerate in 
response to ischemic injury, however whether these cells are derived 
from a resident pool of cardiomyocyte stem cells or from a renewable 
source of circulating bone marrow-derived stem cells that home to 
the damaged myocardium is at present not knovm. Replacement 
and regeneration of functional cardiac muscle after an ischemic 
insult to the heart could be achieved by either stimulating 
proliferation of endogenous mature cardiomyocytes or resident 
cardiac stem cells, or by implanting exogenous donor-derived or 
allogeneic cells such as fetal or embryonic cardiomyocyte precursors, 
bone marrow-derived mesenchymal stem cells, or skeletal myoblasts. 
The newly formed cardiomyocytes must integrate precisely into the 
existing myocardial wall in order to augment synchronized 
contractihty and avoid potentially life-threatening alterations in the 
electrical conduction of the heart. A major impediment to survival of 
the implanted cells is altered immunogenicity by prolonged ex vivo 
culture conditions. In addition, concurrent myocardial 
revascularization is required to ensure viability of the repaired region 
and prevent further scar tissue formation. Human adult bone marrow 
contains endothehal precursors which resemble embryonic 
angioblasts and can be used to induce infarct bed neovascularization 
after experimental myocardial infarction. This results in protection of 
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