p38 alpha activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling. Mus musculus

Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. However, how stress hematopoiesis, including bone marrow transplantation, induces metabolic changes in hematopoietic stem/progenitor cells (HSPCs) remains unclear. Here, we report a critical role for the p38MAPK family isoform p38α in initiating HSPC proliferation during stress hematopoiesis in mouse. We found that p38MAPK is immediately phosphorylated in HSPCs after hematological stress. p38α loss resulted in defective recovery from hematological stress and a delay in initiation of HSPC cycling. Bone marrow transplant altered levels of amino acids and purine-related metabolites in a p38α-dependent manner. Mechanistically, p38α signaling increases expression of inosine-5’-monophosphate dehydrogenase 2 in HSPCs after transplantation, an activity correlated with perturbed cell cycle progression in vitro and in vivo. Overall, we propose a novel mechanism governing HSPC cell cycle initiation via metabolic signaling in response to stress. Overall design: CD34- Flt3- LSK cells (LT-HSC) or CD34+ Flt3+ LSK cells (MPP) in the bone marrow (femur and tibia) from wild type (WT) or p38 cKO (cKO) C57BL/6J mice (Ly5.2) were sorted using SORP FACS AriaI followed by labbeling with CFSE for 30 minutes at 37℃ and transplanted into lethally (9.5Gy)-irradiated Ly5.1 congenic mice. Sixteen hours later, bone marrow cells were collected from femur and tibia of transplanted mice, and CFSE-positive cells were sorted. Total RNA was then extracted using RNeasy micro kit (Qiagen), and cDNA was synthesized from mRNA and hybridized to gene chip Mouse60k (Agilent Technologies) and expression levels analyzed.