In vivo Stem Cell Clonal Dynamics

Tremendous progress has been achieved in the characterization of the hematopoietic system over the past two decades. Historically, the main experimental approach used to elucidate and define these cellular relationships in the bone marrow (BM) has been the transplantation assay. For this reason, most of our knowledge about the in vivo properties of hematopoietic stem cells (HSCs) and progenitor cells has been derived from studies in the transplant context. Because of the lack of tractable systems, the mechanistic nature of non-transplant hematopoiesis has remained largely unexplored. Over the past several years, my laboratory has developed novel genetic tools for the clonal tracing and imaging of hematopoietic populations in the unperturbed niche that aim to bring insight into the biology of stem and progenitor cells in situ. Our work using a transposon-mediated cellular tagging approach indicated that progenitors, and not the classical long-term HSCs, are the cells mainly responsible for the day-to-day production of blood cells in the adult. Our data also suggested that lineage restricted progenitors are the main contributors to hematopoiesis at steady state. These data represent the first systematic analysis of clonal fate in an unperturbed hematopoietic niche and revealed a novel cellular mechanism for homeostatic blood regeneration. We have now utilized this clonal tracing model to bring insight into the dynamics of stem and progenitor biology during embryonic hematopoiesis and in the severely aged hematopoietic system. These data will be discussed at the meeting.