Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.
Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after treatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10,000 to 20,000 microm3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 myocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.
Urbanek
Konrad
K
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Rota
Marcello
M
Cascapera
Stefano
S
Bearzi
Claudia
C
Nascimbene
Angelo
A
De Angelis
Antonella
A
Hosoda
Toru
T
Chimenti
Stefano
S
Baker
Mathue
M
Limana
Federica
F
Nurzynska
Daria
D
Torella
Daniele
D
Rotatori
Francesco
F
Rastaldo
Raffaella
R
Musso
Ezio
E
Quaini
Federico
F
Leri
Annarosa
A
Kajstura
Jan
J
Anversa
Piero
P
D000818:Animals; D002459:Cell Fusion; D002465:Cell Movement / Q000187:drug effects; D003326:Coronary Circulation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D009203:Myocardial Infarction / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D016276:Ventricular Function
D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1