Reprogramming hematopoietic stem cell (HSC) differentiation via metabolic condit

Division Of Basic Sciences - Nci

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Abstract

Hematopoietic stem cell (HSC) maintenance requires high rates of glycolysis and constraints on mitochondrial-based oxidative phosphorylation. Indeed, augmented mitochondrial biogenesis and oxidative phosphorylation result in HSC division and differentiation. Thus, the balance between HSC maintenance and commitment is regulated not only by cytokine-induced signals but by the metabolic state of the cell. Moreover, we and others have recently shown that the utilization and/or inhibition of specific metabolic pathways regulate the commitment of a progenitor to a given lineage fate. Indeed, we identified the utilization of both glutamine and glucose in de novo nucleotide biosynthesis as a sine qua non for erythroid differentiation, defining a new checkpoint between myeloid and erythroid lineage commitment. Present studies are evaluating the functions of nutrient transporters and the metabolic cross-talk between HSPCs and their microenvironment in directing erythroid-myeloid and myeloid-lymphoid differentiation axes via alterations in diverse metabolic networks and the transcriptional/epigenetic states that condition HSPC differentiation. Our overarching hypothesis is that normal human erythropoiesis is dependent on major metabolic changes that interconnect with gene/protein regulation to impact key pathways that result in the generation of a mature red blood cell. Furthermore, we are evaluating the mechanisms via which metabolic control of protein synthesis regulates the erythroid-myeloid lineage commitment of human hematopoietic stem-progenitor cells and contributes to the aberrant differentiation occurring in diseases of ineffective erythropoiesis. In the context of HSC transplantation, autologous or allogeneic progenitors are almost always administered by intravenous injection. They then "home" to the bone marrow (BM) and In order for T cell differentiation to occur, these progenitors must migrate from the BM to the thymus, a process that is regulated by the thymic epithelial cell-mediated secretion of chemokines (CCL25/CCL21). Notably, this migration is a rate-limiting step in T cell reconstitution following HSPC transplantation, due to the adverse effects of chemotherapy/radiation on the thymus. Studies from our own group as well as others have demonstrated the potential to improve thymocyte differentiation by administering HSPCs directly into the thymus. Direct intrathymic (IT) injection of progenitors promotes a more rapid and robust thymopoiesis that requires less input HSPCs, even across histocompatibility barriers. Furthermore, we find that Adeno-associated viral (AAV) vectors allow for efficient gene transfer into developing thymocytes, resulting in the migration of long-lived gene-modified T lymphocytes into the periphery. These studies lay the groundwork for the development of therapies promoting thymic-based strategies to enhance the differentiation of gene-modified T cells post HSPC transplantation.