Microbiota-derived lactate control hematopoiesis and erythropoiesis through regulating stem cell factor from leptin receptor+ niche cells in the bone marrow

Abstract

Abstract Although the functional interplay between the intestinal microbiota and the distant sites beyond the gut have been identified, it is still unveiled how microbiota-derived metabolites are involved in determining the fate of hematopoietic stem cells (HSC). In this study, we are aiming to investigate a role of microbiota-derived lactate in hematopoiesis using G-protein-coupled receptor (Gpr) 81, a known lactate receptor, deficient (Gpr81−/−) mice. We found that total numbers of hematopoietic cells and numbers of Lin−c-Kit+Sca-1+ HSC were significantly reduced in the bone marrow (BM) from Gpr81−/−mice when compared to heterogenic (Gpr81+/−) mice in steady-state condition. Of note, expression levels of stem cell factor (SCF), which is required for maintenance of HSC and erythropoiesis, were significantly decreased in Leptin-receptor expressing (LepR+) stromal cells around sinusoidal vascular of BM tissue obtained from Gpr81−/−mice when compared to those from Gpr81+/− mice. In addition, Gpr81deletion considerably reduced hematopoietic recovery and SCF expression in the BM damaged by irradiation. Oral administration with probiotics or lactate stimulated SCF secretion from LepR+ BM stromal cells and increased hematopoiesis and erythropoiesis. Furthermore, colonization of lactate-producing bacteria in GF mice also accelerated HSC number and SCF expression. Taken together, these results demonstrate that microbiota-derived lactate stimulates SCF secretion by LepR+ BM stromal cells and subsequently activate hematopoiesis and erythropoiesis in a Gpr81-dependent manner.