GABA produced by multiple bone marrow cell types regulates hematopoietic stem and progenitor cells

Summary Hematopoietic stem and progenitor cells (HSPCs) maintain homeostasis of the blood system by balancing proliferation and differentiation. Many extrinsic signals in the bone marrow (BM) microenvironment that regulate this balance are still unknown. We report gamma aminobutyric acid (GABA) metabolite produced in the BM as a regulator of HSPCs. Deletion of the glutamate decarboxylase enzymes (Gad1/2) that produce GABA in either B lineages or endothelial cells (ECs) leads to a moderate reduction in BM GABA levels and HSPC number, suggesting both cell types are GABA sources. However, simultaneous blockade of GABA production from both hematopoietic cells and ECs resulted in a greater reduction of both GABA levels and HSPC numbers. Lower GABA levels in the BM altered the gene expression profile of HSPCs, with expression reduced for proliferation-associated genes and increased for B lineage genes. Our findings suggest GABA from multiple sources coordinates to regulate HSPC activity. Highlights GABA is produced by B cells and endothelial cells in the bone marrow Lower GABA level in the bone marrow reduces HSPC proliferation Lower GABA level primes HSPCs to upregulate B cell differentiation programs eTOC blurb Tamplin and colleagues functionally test production of GABA metabolite in the bone marrow microenvironment as a regulator of hematopoietic stem and progenitor cells. Conditional deletion of GAD enzymes in B cells and endothelial cells demonstrated both are sources of GABA. Lower GABA level primed HSPCs to reduce proliferation and upregulate B cell differentiation programs. Graphical Abstract