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RESEARCH PRODUCT

PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

Ayelet ErezElisabeth NiemeyerSagarika ChakrabartyGuy LedergorGuy LedergorZiv PoratOrit KolletIrit SagiWolfram RufWolfram RufClaudine GrafShiri Gur-cohenAlexander KalinkovichCharles T. EsmonTsvee LapidotEitan WongTomer ItkinAya LudinKarin Golan

subject

Receptors CXCR4Receptors Cell SurfaceADAM17 ProteinIntegrin alpha4beta1BiologyNitric OxideArticleGeneral Biochemistry Genetics and Molecular BiologyMiceBone MarrowCell MovementCell AdhesionmedicineAnimalsReceptor PAR-1Progenitor cellcdc42 GTP-Binding ProteinCell adhesionEndothelial protein C receptorThrombinEndothelial Protein C ReceptorGeneral MedicineHematopoietic Stem CellsChemokine CXCL12Cell biologyMice Inbred C57BLTransplantationADAM ProteinsHaematopoiesismedicine.anatomical_structureCdc42 GTP-Binding ProteinImmunologyBone marrowStem cellProtein CSignal Transduction

description

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein C receptor-positive (EPCR(+)) LT-HSCs in the bone marrow and their recruitment to the blood via two pathways mediated by protease activated receptor 1 (PAR1). Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to EPCR shedding mediated by tumor necrosis factor-α-converting enzyme (TACE), enhanced CXCL12-CXCR4-induced motility and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with activated protein C (aPC) that retains EPCR(+) LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing integrin VLA4 affinity and adhesion. Inhibition of NO production by aPC-EPCR-PAR1 signaling reduces progenitor cell egress from the bone marrow, increases retention of bone marrow NO(low) EPCR(+) LT-HSCs and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR in controlling NO production to balance maintenance and recruitment of bone marrow EPCR(+) LT-HSCs, with potential clinical relevance for stem cell transplantation.

yearjournalcountryeditionlanguage
2015-10-12Nature Medicine
https://doi.org/10.1038/nm.3960