Studying the diversity and epigenetic states of cardiac stem cells after ageing and rejuvenation

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The degree of cardiomyocyte (CM) turnover in the mammalian heart has been controversial although most workers now agree that there is only a very low level of CM replacement during aging and after injury. The origin of new CMs is still unclear, with different studies highlighting potential for proliferation of existing CMs as well stem cell deployment. Stem cell or rejuvenation therapies that achieve enhanced replacement of myocardium and vascular tissue in the wake of ischemic injury would be of enormous benefit to humanity. The Harvey group has previously described a population of colony-forming cells that reside within the CM interstitium and adventitia of coronary arteries in young adult mouse hearts. These cells form mesenchymal stem/stromal cell (MSC)-like cultures akin to those originally described in bone marrow (BM). We hypothesise that cardiac MSC-like cells are a stem cell type analogous to those in BM but with distinct origins and functionalities. We propose that they are dedicated to cardiac homeostasis and repair, acting as a reserve for multiple cell types in the heart, including CMs. They likely additionally act as stress sensors to support CM, vascular tissue and perhaps other stem cell populations through dedicated paracrine functions. The work proposed in this grant addresses the concept of stem cell rejuvenation in aged and compromised tissues. It seeks to understand the diversity and fate of cardiac stem cells in vivo and will explore the epigenetic changes that occur with ageing and stem cell rejuvenation.