Long-Term Outcome of Administration of c-kitPOS Cardiac Progenitor Cells After Acute Myocardial Infarction: Transplanted Cells Do Not Become Cardiomyocytes, Structural and Functional Improvement and Proliferation of Endogenous Cells Persist for at Least One Year
Published Date:Feb 02 2016
Source:Circ Res. 118(7):1091-1105.
Keywords:Adult Stem Cells
Cardiac Progenitor Cells
Hypertrophy, Left Ventricular
In Situ Hybridization, Fluorescence
Proto-Oncogene Proteins C-kit
Rats, Inbred F344
Ventricular Dysfunction, Left
Pubmed Central ID:PMC4818175
Funding:R37 HL055757/HL/NHLBI NIH HHS/United States
HL-78825/HL/NHLBI NIH HHS/United States
R01 HL055757/HL/NHLBI NIH HHS/United States
HL-91202/HL/NHLBI NIH HHS/United States
H75 DP424252/DP/NCCDPHP CDC HHS/United States
HL-113530/HL/NHLBI NIH HHS/United States
HL-74351/HL/NHLBI NIH HHS/United States
P01 HL078825/HL/NHLBI NIH HHS/United States
R01 HL091202/HL/NHLBI NIH HHS/United States
HL-55757/HL/NHLBI NIH HHS/United States
R01 HL074351/HL/NHLBI NIH HHS/United States
UM1 HL113530/HL/NHLBI NIH HHS/United States
R01 HL068088/HL/NHLBI NIH HHS/United States
Cardiac progenitor cells (CPCs) improve left ventricular (LV) remodeling and function after acute or chronic myocardial infarction (MI). However, the long-term (>5 weeks) effects, potential tumorigenicity, and fate of transplanted CPCs are unknown.
To assess the outcome of CPC therapy at 1 year.
METHODS AND RESULTS
Female rats underwent a 90-min coronary occlusion; 4 h after reperfusion, they received intracoronarily vehicle or 1 million male, syngeneic CPCs. One year later, CPC-treated rats exhibited smaller scars and more viable myocardium in the risk region, along with improved LV remodeling and regional and global LV function. No tumors were observed. Some transplanted (Y-chromosomePOS) CPCs (or their progeny) persisted and continued to proliferate, but they failed to acquire a mature cardiomyocyte phenotype and were too few (4-8% of nuclei) to account for the benefits of CPC therapy. Surprisingly, CPC transplantation triggered a prolonged proliferative response of endogenous cells, resulting in increased formation of endothelial cells and Y-chromosomeNEG CPCs for 12 months and increased formation, for at least 7 months, of small cells that expressed cardiomyocytic proteins (α-sarcomeric actin) but did not have a mature cardiomyocyte phenotype.
The beneficial effects of CPCs on LV remodeling and dysfunction are sustained for at least 1 year, and thus are likely to be permanent. Since transplanted CPCs do not differentiate into mature myocytes, their major mechanism of action must involve paracrine actions. These paracrine mechanisms could be very prolonged because some CPCs engraft, proliferate, and persist at 1 year. This is the first report that transplantation of any cell type in the heart induces a proliferative response that lasts at least 1 year. The results strongly support the safety and clinical utility of CPC therapy.
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