[Mitochondrial metabolism and the NADPH-cholesterol axis in hematopoietic stem cell fate determination]

Mitochondrial metabolism actively and precisely contributes to hematopoietic stem cell (HSC) fate determination by ensuring proper segregation of mitochondria and by modulating fatty acid oxidation (FAO) activity and mitochondrial NADPH during asymmetric (or symmetric) cell division. Elevated NADPH levels in HSCs promote anabolic processes, notably cholesterol biosynthesis, redirecting acetyl-CoA away from the TCA cycle toward cholesterol production, which in turn supports multiple downstream biosynthetic pathways essential for HSC maintenance. The NADPH-cholesterol axis facilitates the biogenesis of extracellular vesicles (EVs) to sustain HSC properties. EVs from diverse cell types can influence HSC survival and clonogenic potential, contributing to the maintenance of HSC capacity, including autocrine and paracrine signaling that further reinforces intrinsic regulatory circuits. Targeting the mechanisms that regulate the fate of HSCs remains a central aim of ongoing research in HSC-based therapies, including ex vivo expansion, genetic editing strategies, and the treatment of hematological malignancies, with the potential to enhance transplantation outcomes and patient recovery.