Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function.
The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-c-Met and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas alpha-sarcomeric actin, cardiac myosin heavy chain, troponin I, and alpha-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.
Linke
Axel
A
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Müller
Patrick
P
Nurzynska
Daria
D
Casarsa
Claudia
C
Torella
Daniele
D
Nascimbene
Angelo
A
Castaldo
Clotilde
C
Cascapera
Stefano
S
Böhm
Michael
M
Quaini
Federico
F
Urbanek
Konrad
K
Leri
Annarosa
A
Hintze
Thomas H
TH
Kajstura
Jan
J
Anversa
Piero
P
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D002470:Cell Survival; D004285:Dogs; D004562:Electrocardiography; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D064326:MEF2 Transcription Factors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000032:analysis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1