Loss Of Gpr68 Enhances Hematopoietic Stem Cell Function During Aging

Recent studies implicate metabolic plasticity in fine-tuning hematopoietic stem cell (HSC) homeostasis and function. HSC have been shown to rely on anaerobic glycolysis due to low energetic demand. In contrast, mitochondrial respiration is largely engaged to meet high energetic demand under certain pathophysiological processes, such as differentiation, aging and malignant transformation. The microenvironment, i.e. the HSC niche, has long been known as hypoxic. Glycolytic pathway is not only the metabolic adaptation to the hypoxic niche, but also essential for HSC function at least by providing prosurvival signals. However, glycolysis is reduced in HSC upon aging, which is associated with diminished regeneration ability of HSC. How glycolysis impacts HSC biology is unclear. G protein-coupled receptor 68 (GPR68, also known as OGR1) responds to extracellular acidosis, activating the phospholipase C (PLCb)/calcium pathway or the adenylyl cyclase (CA)/cAMP pathway. The end point product of glycolysis is lactate that leads to extracellular acidosis. This prompts us to examine the role of Gpr68 in HSC biology.