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Monitoring Stem Cell Research 
differentiation, and replicative senescence is due to negative 
regulation of cell cycle progression by two functionally distinct 
families of Cdk inhibitors, the Ink4 and Cip/Kip families The cell 
cycle inhibitory activity of p21Cipl/WAFl is intimately correlated 
with its nuclear localization and participation in quaternary 
complexes of cell cycle regulators by binding to G1 cyclin-CDK 
through its N-terminal domain and to proliferating cell nuclear 
antigen (PCNA) through its C-terminal domain The latter 
interaction blocks the ability of PCNA to activate DNA polymerase, 
the principal replicative DNA polymerase For a growth-arrested 
cell to subsequently enter an apoptotic pathway requires signals 
provided by specific apoptotic stimuli in concert with cell-cycle 
regulators. For example, caspase-mediated cleavage of p21, together 
with upregulation of cyclin A-associated cdk2 activity, have been 
shown to be critical steps for induction of cellular apoptosis by either 
deprivation of growth factors or hypoxia of cardiomyocytes 
Throughout life, a mixture of young and old cells is present in 
the normal myocardium. Although most myocytes seem to be 
terminally differentiated, there is a fraction of younger myocytes (15- 
20%) that retains the capacity to replicate Moreover, recent 
observations have suggested that some human ventricular 
cardiomyocytes also have the capacity to proliferate and regenerate 
in response to ischemic injury The dividing myocytes can be 
identified on the basis of immunohistochemical staining of 
proliferating nuclear structures such as Ki67 and cell surface 
expression of specific surface markers, including c-kit (GDI 17). 
Whether these cells are derived firom a resident pool of 
cardiomyocyte stem cells or are derived from a renewable source of 
circulating bone marrow-derived stem cells that home to the 
damaged myocardium remains to be determined. More importantly, 
the signals required for homing, in situ expansion and differentiation 
of these cells are, at present, unknown. Gaining an understanding of 
these issues would open the possibility of manipulating the biology 
of endogenous cardiomyocytes in order to augment the healing 
process after myocardial ischemia. 
Strategies For The Use Of Cellular Therapy To Improve Myocardial 
Function. 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 cardiomyocytes. The newly 
formed cardiomyocytes must integrate precisely into the existing 
PRE-PUBLICATION VERSION 
