Cardiac-Resident PDGFRa+ Sca1+ Mesenchymal Progenitors Regulate the Development of Fibrosis in the Heart

Heart failure remains the number one cause of mortality in the Western world. Cardiac fibrosis, or scarring of the heart, is understood to be an important cause of deterioration of heart function and is observed in most cardiac disease. Despite its recognized importance, the cellular and molecular mechanisms leading to the cardiac fibrosis are still poorly understood. A cell type called cardiac fibroblasts, which are supportive cells of the heart, are known to be involved but difficulty in identifying these cells within the body have hampered efforts to modulate their involvement in fibrosis. Clearly, novel therapeutic strategies to prevent the formation and/or reduce existing cardiac fibrosis require a greater understanding of supportive cell populations within the heart. Our lab has recently identified a new supportive stem cell population termed fibro/adipogenic progenitors (FAPs), within skeletal muscle which gives rise to the characteristics "fibrofatty" infiltrate (scarring and formation of fat) in regeneration of repeatedly damaged muscle. Data from these studies have further demonstrated their vital role in regulating both muscle regeneration and formation of fibrosis following experimentally induced muscle damage. My experiments have demonstrated a similar mesenchymal progenitor population is harbored in the heart. Following enzymatic digestion of the heart, CD31-;CD45-;PDGFRa+;Sca1+ were isolated from the heart using fluorescence activated cell sorting, clonally expanded and differentiated into both osteogenic and adipogenic lineages. qRT-PCR analysis of gene expression in this population relative to other CD31-;CD45- populations showed that they expressed genes associated with extra-cellular matrix (CTGF, collagen 1 & 3, TGF-B1) preferentially over other cardiac populations, a trend which increased follow experimentally induced cardiac fibrosis using isoproterenol infusion. Relative number of PDGFRa+;Sca1+ cells increased following induction of fibrosis, and was also observed to be greatly increased aged mdx mice, a genetic model of cardiac fibrosis. Using imatinib mesylate, inhibition of cardiac PDGFRa+ Sca1+ cell proliferation (asssessed via EdU incorporation) as well as differentiation led to a reduction in cardiac fibrosis in both models of fibrosis. We conclude that the heart harbors a novel mesenchymal progenitor population and demonstrated its role in the formation of fibrosis in the heart. Further elucidation of the role of cardiac PDGFRa+;Sca1+ cells in the development of cardiac fibrosis will provide new therapeutic targets to modulate this process, and improve long-term survival of patients suffering from a wide variety of cardiomyopathies.