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

P. V. Anu, Shubham Haribhau Mehatre, Catherine M. Verfaillie, Mohammad Tauqeer Alam, Satish Khurana

Research output: Contribution to journalArticlepeer-review

Abstract

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 midgestation 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.

Original languageEnglish
Article numbereadh8478
JournalScience advances
Volume10
Issue number7
DOIs
Publication statusPublished - 2024

ASJC Scopus subject areas

  • General

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