Endothelial protein C receptor signaling regulates myeloid-biased hematopoiesis under stress and in aging

Introduction Hematopoietic stem and progenitor cells (HSPC) replenish all mature blood cells to meet the host’s adaptive demand. We showed an important role for the endothelial protein C receptor (EPCR) in maintaining HSC quiescence via integrin α4β1 (VLA4), the small GTPase Cdc42 and PAR (protease-activated receptor) 1 in the bone marrow (BM). To discriminate functions of EPCR in anticoagulation versus signaling, we studied EPCRC/S mice carrying a single intracellular point mutation abolishing normal trafficking of EPCR through endo-lysosomal compartments. We assessed the contributions of EPCR signaling to stem cell maintenance by analyzing HSPC during mobilization, myeloablation and aging. Moreover, we compared the phenotype of EPCRC/S and PAR1 mutants with selective protease resistance, namely PAR1R41Q and PAR1R46Q mice.