The Role of Human Blood-Vessel-Derived Stem Cells in Tissue Repair and Regeneration

Multipotent stem/progenitor cells have been identified in nearly all vascularized organs in the human body. Our research group recently discovered that human blood vessels harbor various stem/progenitor cell populace of mesodermal lineage, exhibiting common multi-lineage differentiation capacity and yet distinct cell lineage markers. Specifically, each of the three structural layers of blood vessels: intima, media, and adventitia, have been found to respectively include one of the three populations of precursor cells: myogenic endothelial cells (MECs), pericytes, and adventitial cells (ACs). Our studies have independently characterized each of “Three Musketeers” and evaluated their myogenic capacity. Nevertheless, the therapeutic potential of pericytes in cardiac repair remains unknown, and whether pericytes natively residing in human heart possess similar stem cell characteristics and multipotency has not been investigated. Moreover, none of our prior studies has directly compared the regenerative efficacy between subpopulations of blood-vessel-derived stem cells (BVSCs), nor did we explore any alternative source, other than fresh tissue biopsies, to isolate BVSCs. \ud My dissertation study aims to understand the role of subpopulations of BVSCs, pericytes in particular, and their relative efficiency in tissue repair/regeneration, with emphases in myocardial infarction and skeletal muscle injury. Specifically, my work has three independent yet related focuses: (I) to investigate the therapeutic efficacy of human pericyte transplantation and associated mechanisms of action in ischemic heart repair; (II) to characterize native human heart pericytes and examine whether tissue specificity exists between pericytes of different tissue origins; (III) to directly compare the myogenic potential between subpopulations of BVSCs and explore alternative source(s) of BVSCs that are more clinically accessible for skeletal muscle repair. \ud The results of my studies showed that transplantation of human skeletal muscle-derived pericytes (SkMPs) repair the infarcted hearts more effectively than control and myoblast groups with their multiple restorative effects under hypoxia, including angiogenesis, anti-fibrosis, and anti-inflammation. Resident human heart pericytes (HPs) shared common similarity with pericytes of other tissues, such as typical pericyte and MSC marker expression, cell growth pattern in culture, and certain mesodermal developmental potential. Nevertheless, HPs differ from SkMPs in the lack of skeletal myogenic potential and differential angiogenic response under hypoxia, tissue-specific phenomena that were not observed previously. Additionally, in terms of skeletal myogenesis, MECs demonstrated superior efficiency to pericytes in vitro and in vivo. Finally, MECs and pericytes purified from long-term cryopreserved primary human muscle culture by cell sorting exhibited similar myogenic potential in vivo to their counterparts isolated from fresh biopsies, indicating cryopreservation of unpurified cells may serve as an alternative source of therapeutic myogenic precursors. \u