Models Of Stem Cell Transplantation For The Repair Of Non-Hematopoietic Tissues

Abstract

Human stem cells from adult sources have been shown, in our laboratory and others, to promote the repair of damaged tissues. Different populations of stem cells contribute to the regeneration of muscle, neural tissue, liver, heart, and vasculature, although the mechanisms by which they accomplish this are still not well understood. We and others have shown that stem cells home to hypoxic and/or inflamed areas, and release bioactive factors that can suppress the local immune system, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate recruitment, retention, mitosis and differentiation of endogenous tissue-residing stem cells. These trophic effects are distinct from the direct differentiation of stem cells into the tissue to be regenerated. To actually rebuild a non-hematopoietic tissue, the differentiated progeny of embryonic or induced pluripotent stem cells will be required. We have focused on improving rodent models in which to examine human stem cell-mediated disease correction and tissue repair, focusing primarily on liver regeneration and hypoxic tissue models of peripheral vascular disease and cardiac ischemia. Most recently we are studying mesenchymal stem cell–mediated repair of neural damage. We are interested in the mechanisms by which stem cells of different types and origins home preferentially into areas of tissue damage, and we seek to improve the robustness. To track cells into the damaged tissues in vivo, we have labeled them with fluorophore – conjugated iron oxide nanoparticles and have used novel mouse models that facilitate human cell detection. We have also used 19F magnetic resonance imaging for stem cell tracking with multiple unique perfluorocarbon nanobeacons, human/murine centromeric FISH, immunohistochemistry and quantitative PCR. Using these technologies, we have shown that human stem cells migrate from the bloodstream randomly and in moderate numbers throughout all tissues examined in cases of chronic disease or following sublethal irradiation, but that in instances of acute damage, the homing is more vigorous and specific to the site of damage. Pre-culture in hypoxia dramatically alters the phenotype and migratory characteristics of human mesenchymal stem cells. We are applying this knowledge to tissue repair strategies, to allow enhanced numbers of stem cells to migrate to the areas of hypoxic damage, to exert trophic effects that initiate revascularization and cascades of repair. Human stem cells from adult sources have been shown, in our laboratory and others, to promote the repair of damaged tissues. Different populations of stem cells contribute to the regeneration of muscle, neural tissue, liver, heart, and vasculature, although the mechanisms by which they accomplish this are still not well understood. We and others have shown that stem cells home to hypoxic and/or inflamed areas, and release bioactive factors that can suppress the local immune system, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate recruitment, retention, mitosis and differentiation of endogenous tissue-residing stem cells. These trophic effects are distinct from the direct differentiation of stem cells into the tissue to be regenerated. To actually rebuild a non-hematopoietic tissue, the differentiated progeny of embryonic or induced pluripotent stem cells will be required. We have focused on improving rodent models in which to examine human stem cell-mediated disease correction and tissue repair, focusing primarily on liver regeneration and hypoxic tissue models of peripheral vascular disease and cardiac ischemia. Most recently we are studying mesenchymal stem cell–mediated repair of neural damage. We are interested in the mechanisms by which stem cells of different types and origins home preferentially into areas of tissue damage, and we seek to improve the robustness. To track cells into the damaged tissues in vivo, we have labeled them with fluorophore – conjugated iron oxide nanoparticles and have used novel mouse models that facilitate human cell detection. We have also used 19F magnetic resonance imaging for stem cell tracking with multiple unique perfluorocarbon nanobeacons, human/murine centromeric FISH, immunohistochemistry and quantitative PCR. Using these technologies, we have shown that human stem cells migrate from the bloodstream randomly and in moderate numbers throughout all tissues examined in cases of chronic disease or following sublethal irradiation, but that in instances of acute damage, the homing is more vigorous and specific to the site of damage. Pre-culture in hypoxia dramatically alters the phenotype and migratory characteristics of human mesenchymal stem cells. We are applying this knowledge to tissue repair strategies, to allow enhanced numbers of stem cells to migrate to the areas of hypoxic damage, to exert trophic effects that initiate revascularization and cascades of repair.