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Transplantation of endogenous cardiac progenitors into the infarcted heart is currently being examined as a cell–based therapy to reverse tissue damage. Early stem cell loss and limited regenerative capacity reduces the efficacy of cell types currently used for cell based treatment. We tested the hypothesis that a novel population of early cardiovascular stem cells isolated from cardiac tissue will facilitate cardiac regeneration after myocardial infarction.Cardiovascular progenitor cell clones expressing Isl-1, mesp-1, brachyury, c-kit, and SSEA1 were isolated from neonatal humans and a comparable population was isolated from neonatal Suffolk sheep for use in an allotransplantation model of stem cell-based cardiac repair. A myocardial infarction was introduced by LAD coronary artery ligation. Ten million neonatal sheep cardiovascular progenitor cells were labeled for tracking and introduced as a clonal population by direct cardiac injection at 3-4 weeks post-myocardial infarction. Cardiovascular progenitor cell retention was quantified two months post-injection, and immunostaining was done to assess stem cell retention, proliferation, and differentiation after transplantation in vivo. PCR was used to identify paracrine factors released during cardiovascular repair. Functional changes were assessed by echocardiogram.Cardiovascular progenitor cells survived, proliferated and differentiated in vivo into cardiac myocytes and endothelial cells at the site of repair following myocardial infarction. Donor cells that were retained in the infarct zone at two months post-transplant were quantified and included newly introduced cardiovascular progenitor cells that continued to divide. Differentiation into cardiomyocytes and endothelial cells was also quantified by dual immunostaining. The majority of progenitor cells differentiated into cardiomyocytes whereas the elevated number of endothelial cells localized at the site of repair were predominantly host-derived, suggesting that endothelial cells in the regenerating area are recruited in response to paracrine factors. Transcripts encoding VEGF, CXCL12, IGF-1 and HGF were induced. Notch and AKT signaling were elevated and a significant improvement in ejection fraction and fractional shortening was shown two months after allogeneic cardiovascular progenitor cell transplantation in this model.Neonatal islet-1+ early cardiovascular progenitor cells co-expressing mesp-1, brachyury, c-kit, and SSEA1 are retained, divide and differentiate when introduced for cardiac repair in vivo and can be isolated and rapidly expanded from cardiovascular tissue. Clonal populations with these markers represent a promising cell type for cardiac repair.GCAT Loma Linda University.