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

哺乳动物心脏中心肌细胞（CM）的更替程度一直存在争议，尽管大多数研究人员现在都认为，在衰老和损伤后，CM的更替水平非常低。新的CMs的起源仍然不清楚，不同的研究强调了现有CMs的增殖和干细胞部署的潜力。在缺血性损伤后实现心肌和血管组织增强替代的干细胞或再生疗法将对人类产生巨大的益处。Harvey小组先前描述了一群集落形成细胞，它们存在于年轻成年小鼠心脏的冠状动脉间质和外膜中。这些细胞形成间充质干细胞/基质细胞（MSC）样培养物，类似于最初在骨髓（BM）中描述的细胞。我们假设心脏间质干细胞样细胞是一种类似于骨髓干细胞的干细胞类型，但具有不同的起源和功能。我们认为它们致力于心脏稳态和修复，作为心脏多种细胞类型的储备，包括CMs。它们可能还作为压力传感器，通过专门的旁分泌功能支持CM、血管组织和其他干细胞群。在这项拨款中提出的工作解决了衰老和受损组织中干细胞再生的概念。它旨在了解心脏干细胞在体内的多样性和命运，并将探索随着衰老和干细胞再生而发生的表观遗传变化。

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.