Myocardial neovascularization by bone marrow angioblasts results in cardiomyocyte regeneration.
The primary cardiac response to ischemic insult is cardiomyocyte hypertrophy, which initiates a genetic program culminating in apoptotic myocyte loss, progressive collagen replacement, and heart failure, a process termed cardiac remodeling. Although a few cardiomyocytes at the peri-infarct region can proliferate and regenerate after injury, no approaches are known to effectively induce endogenous cardiomyocytes to enter the cell cycle. We recently isolated, in human adult bone marrow, endothelial progenitor cells, or angioblasts, that migrate to ischemic myocardium, where they induce neovascularization and prevent myocardial remodeling. Here we show that increasing the number of angioblasts trafficking to the infarct zone results in dose-dependent neovascularization with development of progressively larger-sized capillaries. This results in sustained improvement in cardiac function by mechanisms involving protection against apoptosis and, strikingly, induction of proliferation/regeneration of endogenous cardiomyocytes. Our results suggest that agents that increase myocardial homing of bone marrow angioblasts could effectively induce endogenous cardiomyocytes to enter the cell cycle and improve functional cardiac recovery.
Schuster
M D
MD
Department of Surgery and Medicine, Columbia University, New York, New York 10032, USA.
Kocher
A A
AA
Seki
T
T
Martens
T P
TP
Xiang
G
G
Homma
S
S
Itescu
S
S
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D002470:Cell Survival; D017690:Cell Transplantation; D003331:Coronary Vessels / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology*; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology; D006801:Humans; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D011923:Rats, Nude; D013234:Stem Cells / Q000166:cytology*; D014183:Transplantation, Heterologous