Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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Authors: | Leal Oburoglu Els Mansell Isaac Canals Valgardur Sigurdsson Carolina Guibentif Shamit Soneji NielsBjarne Woods |
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Institution: | 1. Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund Sweden ; 2. Neurology, Lund Stem Cell Center, Lund University, Lund Sweden ; 3. Molecular Hematology, Lund Stem Cell Center, Lund University, Lund Sweden ;4.Present address: Sahlgrenska Center for Cancer Research, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg Sweden |
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Abstract: | During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial‐to‐hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis‐mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS‐mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation. |
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Keywords: | endothelial‐ to‐ hematopoietic transition glycolysis hematopoiesis OXPHOS pyruvate metabolism |
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