Significance: The effect of redox signaling on hematopoietic stem cell (HSC) function is not clearly understood.
Recent advances: A growing body of evidence suggests that adult HSCs reside in the hypoxic bone marrow microenvironment or niche during homeostasis. It was recently shown that primitive HSCs in the bone marrow prefer to utilize anaerobic glycolysis to meet their energy demands and have lower rates of oxygen consumption and lower ATP levels. Hypoxia-inducible factor-α (Hif-1α) is a master regulator of cellular metabolism. With hundreds of downstream target genes and crosstalk with other signaling pathways, it regulates various aspects of metabolism from the oxidative stress response to glycolysis and mitochondrial respiration. Hif-1α is highly expressed in HSCs, where it regulates their function and metabolic phenotype. However, the regulation of Hif-1α in HSCs is not entirely understood. The homeobox transcription factor myeloid ecotropic viral integration site 1 (Meis1) is expressed in the most primitive HSCs populations, and it is required for primitive hematopoiesis. Recent reports suggest that Meis1 is required for normal adult HSC function by regulating the metabolism and redox state of HSCs transcriptionally through Hif-1α and Hif-2α.
Critical issues: Given the profound effect of redox status on HSC function, it is critical to fully characterize the intrinsic, and microenvironment-related mechanisms of metabolic and redox regulation in HSCs.
Future directions: Future studies will be needed to elucidate the link between HSC metabolism and HSC fates, including quiescence, self-renewal, differentiation, apoptosis, and migration.