Glycolytic state of aortic endothelium favors hematopoietic transition during the emergence of definitive hematopoiesis

• DOI: 10.1126/sciadv.adh8478
• Publication Date: 2024-02-16T18:59:17Z
• Authors: Anu PV; Shubham Haribhau ...; Catherine M. Verf...; Mohammad Tauqeer ...; Satish Khurana
• Keywords: Proteomics; Mammals; Tandem Mass Spectrometry; Animals; Biomedicine and Life Sciences; Endothelium, Vascular; Hematopoietic Stem Cells; Hematopoiesis

The first definitive hematopoietic progenitors emerge through the process of endothelial-to-hematopoietic transition in vertebrate embryos. With molecular regulators for this process worked out, the role of metabolic pathways used remains unclear. Here, we performed nano–LC-MS/MS–based proteomic analysis and predicted a metabolic switch from a glycolytic to oxidative state upon hematopoietic transition. Mitochondrial activity, glucose uptake, and glycolytic flux analysis supported this hypothesis. Systemic inhibition of lactate dehydrogenase A (LDHA) increased oxygen consumption rate in the hemato-endothelial system and inhibited the emergence of intra-aortic hematopoietic clusters. These findings were corroborated using Tie2-Cre –mediated deletion of Ldha that showed similar effects on hematopoietic emergence. Conversely, stabilization of HIF-1α via inhibition of oxygen-sensing pathway led to decreased oxidative flux and promoted hematopoietic emergence in mid-gestation embryos. Thus, cell-intrinsic regulation of metabolic state overrides oxygenated microenvironment in the aorta to promote a glycolytic metabolic state that is crucial for hematopoietic emergence in mammalian embryos.