Identification of a coronary vascular progenitor cell in the human heart.
Primitive cells capable of generating small resistance arterioles and capillary structures in the injured myocardium have been identified repeatedly. However, these cells do not form large conductive coronary arteries that would have important implications in the management of the ischemic heart. In the current study, we determined whether the human heart possesses a class of progenitor cells that regulates the growth of endothelial cells (ECs) and smooth muscle cells (SMCs) and vasculogenesis. The expression of vascular endothelial growth-factor receptor 2 (KDR) was used, together with the stem cell antigen c-kit, to isolate and expand a resident coronary vascular progenitor cell (VPC) from human myocardial samples. Structurally, vascular niches composed of c-kit-KDR-positive VPCs were identified within the walls of coronary vessels. The VPCs were connected by gap junctions to ECs, SMCs, and fibroblasts that operate as supporting cells. In vitro, VPCs were self-renewing and clonogenic and differentiated predominantly into ECs and SMCs and partly into cardiomyocytes. To establish the functional import of VPCs, a critical stenosis was created in immunosuppressed dogs, and tagged human VPCs were injected in proximity to the constricted artery. One month later, there was an increase in coronary blood flow (CBF) distal to the stenotic artery, resulting in functional improvement of the ischemic myocardium. Regenerated large, intermediate, and small human coronary arteries and capillaries were found. In conclusion, the human heart contains a pool of VPCs that can be implemented clinically to form functionally competent coronary vessels and improve CBF in patients with ischemic cardiomyopathy.
Bearzi
Claudia
C
Department of Anesthesia and Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Leri
Annarosa
A
Lo Monaco
Francesco
F
Rota
Marcello
M
Gonzalez
Arantxa
A
Hosoda
Toru
T
Pepe
Martino
M
Qanud
Khaled
K
Ojaimi
Caroline
C
Bardelli
Silvana
S
D'Amario
Domenico
D
D'Alessandro
David A
DA
Michler
Robert E
RE
Dimmeler
Stefanie
S
Zeiher
Andreas M
AM
Urbanek
Konrad
K
Hintze
Thomas H
TH
Kajstura
Jan
J
Anversa
Piero
P
D000199:Actins / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology* / Q000502:physiology / Q000637:transplantation; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D018031:Connexin 43 / Q000378:metabolism; D003326:Coronary Circulation; D023921:Coronary Stenosis / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D003331:Coronary Vessels / Q000166:cytology* / Q000503:physiopathology; D004285:Dogs; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C541116:ACTA2 protein, human; D000199:Actins; D018031:Connexin 43; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2