Abstract
Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT–PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα+ cells. Clonal progeny of single Sca1+ SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα− cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα+/CD31− cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα−/CD31+ cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1+ stem/progenitor cell.
Highlights
Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though-relationships among reported cells remain obscure
Fate-mapping studies provide evidence that adult mammalian cardiac regeneration exists, though at a level insufficient to rescue damaged hearts, occurring at least partly through a lineage decision by progenitor/stem cells[1,2,3,4], not proliferation of pre-formed myocytes as in zebrafish or newborn mice[5,6]. This view is supported by evidence using transgenic fluorescent anillin, that cardiomyocytes in damaged adult hearts increase in ploidy but do not divide[7]
Adult cardiac Lin À /Sca[1] þ cells were isolated by immunomagnetic purification, further purified by flow cytometry (Fig. 1a, left), and stained with Hoechst 33342 (Fig. 1a, centre, right)
Summary
Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Fate-mapping studies provide evidence that adult mammalian cardiac regeneration exists, though at a level insufficient to rescue damaged hearts, occurring at least partly through a lineage decision by progenitor/stem cells[1,2,3,4], not proliferation of pre-formed myocytes as in zebrafish or newborn mice[5,6]. Fate mapping with R26R-Confetti, which labels clonal derivatives randomly with one of four fluorescent proteins[25], suggests that most single Sca[1] cells have limited expansion potential and give rise to a single cell type[3] Given this rare clonogenic potential, infrequent differentiation and variable expression of other markers[8,9,12,26], Sca[1] þ cells, if not further refined, are presumptively heterogeneous. Relative to MSCs from other tissues, cCFU-Fs express greater Mef2c, but lack most cardiogenic transcription factors[26]
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