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Research efforts in my laboratory are focused on the physio-pathological potential of hematopoietic stem cells (HSCs). The adult bone marrow is thought to contain at least two discernible stem cell populations: HSCs, defined by their capability of hematopoietic reconstitution in vivo, and mesenchymal stromal cells (MSC), originally defined by their in vitro potential to differentiate into mesenchymal tissue cells including fibroblasts, fat, cartilage, and bone. Recent studies suggest that organs once thought to be incapable of regenerative ability may indeed be capable of regeneration and repair via stem cells. While the potential of stem cells is clear from studies in which unfractionated or unpurified populations of bone marrow are transplanted, due to technical challenges, controversies have resulted when attempts are made to assign specific potentials to HSCs or MSCs. This has led to the need for stringent, well-defined lineage tracing methods. To this end, my laboratory has developed a transplantation model in which the bone marrow of lethally irradiated recipient mice is reconstituted by a clonal population of cells derived from a single HSC that expresses enhanced green fluorescent protein. This transplantation model is technically complex and experimentally challenging, with only a few laboratories worldwide capable of executing such a transplantation scheme. Our work also employs novel transgenic models to discern HSC-derived cells in tissues. With an eye towards translational potential, we also employ xenograft models to investigate the role(s) of human HSCs. The development of these tools has allowed my laboratory, my mentees, and my collaborators to conduct paradigm-shifting studies of the roles of HSCs in health and disease. Together, these approaches have resulted in discovery of novel roles for HSC and HSC-derived cells in a variety of pathological conditions that directly impact human health, including cancer, cardiovascular disease, pulmonary fibrosis, and orthopedic injury and repair.