Depicting human endothelial to hematopoietic transition and the effects of modulating pyruvate catabolism on blood formation

Hematopoietic stem cell (HSC) quiescence, maintenance and differentiation are closely linked to changes in metabolism. However, the role of metabolism during the first emergence of HSCs from hemogenic endothelium (HE) is still unknown. In this study, we focus on the implication of energetic metabolic pathways during endothelial to hematopoietic transition (EHT). EHT is accompanied by a metabolic switch, with concomitant increases in glycolysis and oxidative phosphorylation (OXPHOS). Inhibiting glycolysis in HE cells leads to a block in hematopoietic lineage specification. An OXPHOS fuel, glutamine, is essential for HSC emergence and provides distinct intermediates to mediate differentiation towards the two major hematopoietic lineages, GPA+ and CD45+ cells. Strikingly, shifting the fate of pyruvate from glycolysis to the TCA cycle redirects HE specification towards CD45+ cells at the expense of GPA+ cells and vice versa. As such, our findings reveal the plasticity of hematopoietic lineage specification during EHT which can be modulated by metabolism. Transcriptomic analysis of hiPSC-derived HE, EHT, HSC-like cells and cord blood CD34+ cells. Comparison of control HE cells with UK5099- or DCA-treated HE cells. ***Raw data not provided due to patient privacy concerns***