Formation of large coronary arteries by cardiac progenitor cells.
Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1alpha, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.
Tillmanns
Jochen
J
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Rota
Marcello
M
Hosoda
Toru
T
Misao
Yu
Y
Esposito
Grazia
G
Gonzalez
Arantxa
A
Vitale
Serena
S
Parolin
Carola
C
Yasuzawa-Amano
Saori
S
Muraski
John
J
De Angelis
Antonella
A
Lecapitaine
Nicole
N
Siggins
Robert W
RW
Loredo
Maria
M
Bearzi
Claudia
C
Bolli
Roberto
R
Urbanek
Konrad
K
Leri
Annarosa
A
Kajstura
Jan
J
Anversa
Piero
P
D000818:Animals; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D017202:Myocardial Ischemia / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018919:Neovascularization, Physiologic; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*
D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019009:Proto-Oncogene Proteins c-kit