Metabolic programs regulating hematopoietic stem cell differentiation

Division Of Basic Sciences - Nci

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Abstract

Hematopoietic stem cells (HSCs) possess the remarkable capacity to both self-renew and differentiate into all mature blood lineages. Historically, the signals guiding these fate decisions were primarily attributed to cytokines and the bone marrow microenvironment. However, accumulating evidence highlights the pivotal role of cellular metabolism and nutrient transport in shaping lineage commitment and functional differentiation. Our research integrates metabolic, transcriptional, and immunologic perspectives to uncover how these factors coordinate hematopoietic development and function. We have identified key nutrient dependencies that influence erythroid differentiation, including glucose and glutamine utilization for nucleotide synthesis and arginine uptake via SLC7A1/CAT1. In collaboration with Dr. S. Azouzi's group, we found that impaired nucleoside uptake due to ENT1 mutations can be genetically compensated by loss-of-function in the cyclic nucleotide exporter ABCC4, highlighting the interconnectedness of nucleoside flux and erythroid maturation. Additionally, in collaboration with Dr. S. Kinet and P. Gonzalez-Menendez, we recently identified a lineage-specific requirement for SLC7A1/CAT1-mediated arginine uptake in erythroid, but not myeloid, differentiation. This effect is mediated through arginine-dependent hypusination of eIF5A, a post-translational modification essential for the translation of a large subset of mitochondrial-targeted proteins. Importantly, this SLC7A1-eIF5A-mitochondrial axis is disrupted in ribosomopathies such as myelodysplastic syndrome (MDS) and Diamond-Blackfan anemia, establishing a novel link between ribosomal integrity, mitochondrial metabolism, and cell fate commitment. Our collaborative studies with Dr. Dan Larson have also illuminated how mutations in splicing factors such as U2AF1 can reshape mitochondrial metabolism. Indeed, they discovered that U2AF1 not only regulates nuclear RNA splicing but also controls the localization and translation of mitochondrial mRNAs at the outer mitochondrial membrane. U2AF1 mutations were found to be associated with mitochondrial structural changes and a significantly increased dependence on oxidative phosphorylation-phenotypes echoed in patient-derived MDS samples. These results point to an unexpected coupling between RNA splicing, mitochondrial mRNA localization, and metabolic rewiring in hematologic malignancies. In parallel, we are developing strategies to enhance T-cell reconstitution following hematopoietic stem/progenitor cell (HSPC) transplantation, particularly for patients with congenital immunodeficiencies. Traditional IV transplantation relies on bone marrow homing and subsequent thymic seeding, which can be inefficient in severely immunodeficient hosts. In collaboration with Dr. V. Zimmermann, we have shown that intrathymic (IT) injection of HSPCs bypasses this bottleneck, enabling robust and durable thymus-autonomous T cell development. In ZAP-70-deficient mice, IT HSPC transplantation led to rapid and sustained thymic reconstitution, including the development of FOXP3+ regulatory T cells and restoration of the thymic medulla. Strikingly, we found that donor-derived RORgT+ group 3 innate lymphoid cells (ILC3s) are required for medullary thymic epithelial cell (mTEC) maturation and thymic niche regeneration, revealing a novel ILC3-mTEC axis essential for T cell reconstitution. Together, our work illustrates how metabolic, translational, and post-transcriptional mechanisms converge to regulate physiological and pathological hematopoietic lineage specification. These insights lay the groundwork for novel therapeutic strategies aimed at targeting metabolic vulnerabilities, enhancing thymic regeneration, and correcting lineage-specific defects in inherited and acquired hematologic disorders.