Glycolytic state of aortic endothelium favors hematopoietic transition during the emergence of definitive hematopoiesis.
Anu PvShubham Haribhau MehatreCatherine M VerfaillieMohammad Tauqeer AlamSatish KhuranaPublished in: Science advances (2024)
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.
Keyphrases
- bone marrow
- aortic valve
- endothelial cells
- pulmonary artery
- left ventricular
- stem cells
- preterm infants
- squamous cell carcinoma
- metabolic syndrome
- mesenchymal stem cells
- type diabetes
- transcription factor
- coronary artery
- heart failure
- radiation therapy
- blood pressure
- pulmonary hypertension
- cell therapy
- locally advanced
- insulin resistance
- single molecule
- rectal cancer