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

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 genes encoding the glutamate decarboxylase enzymes (Gad1 and Gad2) that produce GABA in either B lineages or endothelial cells (ECs) led to a slight reduction in BM HSPCs but not GABA levels. However, simultaneous blockade of GABA production from both hematopoietic cells and ECs resulted in a greater reduction of HSPCs and a significant reduction of BM GABA levels. 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.