Metabolic programs regulating hematopoietic stem cell differentiation

Division Of Basic Sciences - Nci

Investigators

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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. More recently, we have identified fuel resource availability as a critical regulator of HSC commitment and differentiation to distinct lineage fates. Glutamine entry via the ASCT2 transporter fuels erythroid specification via nucleotide biosynthesis and blocking glutaminolysis diverts HSCs to the myelomonocytic lineage Indeed, we recently found that patients with metabolic defects in the ENT1 nucleoside transporter exhibit erythroid defects. Moreover, we have identified SLC7A1/CAT1-mediated transport of arginine as a regulator of erythroid, but not myeloid, lineage differentiation of human progenitor cells via eIF5A hypusination, promoting protein synthesis. Of note, this pathway is defective in patients with mutations in ribosomal protein genes, including myelodysplastic syndrome and Diamond Blackfan anemia. These results highlight the role of nutrient transport/ utilization as regulators of HSC development and support ongoing studies assessing the mechanisms via which alterations in metabolic reprogramming contribute 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. While HSC then "home" to the bone marrow (BM), these progenitors must migrate from the BM to the thymus in order for T cell differentiation to occur. Notably, this migration, regulated by thymic epithelial cell-mediated secretion of chemokines (CCL25/CCL21) 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. Most recently, we have found that intrathymic AAV gene transfer results in a site-specific integration of AAV genomes into the TCR locus, achieving long-term gene transfer in T lymphocytes. 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.