title: Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling.
abstract: The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/protease-activated receptor-1 (PAR1) signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation. Recent studies define two new PAR1-mediated signaling cascades that regulate EPCR(+) LT-HSC BM retention and egress. EPCR/PAR1 signaling facilitates LT-HSC BM repopulation, retention, survival, and chemotherapy resistance by restricting nitric oxide (NO) production, maintaining NO(low) LT-HSC BM retention with increased VLA4 expression, affinity, and adhesion. Conversely, acute stress and clinical mobilization upregulate thrombin generation and activate different PAR1 signaling that overcomes BM EPCR(+) LT-HSC retention, inducing their recruitment to the bloodstream. Thrombin/PAR1 signaling induces NO generation, TACE-mediated EPCR shedding, and upregulation of CXCR4 and PAR1, leading to CXCL12-mediated stem and progenitor cell mobilization. This review discusses new roles for factors traditionally viewed as coagulation related, which independently act in the BM to regulate PAR1 signaling in bone- and blood-forming progenitor cells, navigating their fate by controlling NO production.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Gur-Cohen
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.affiliation: Center for Thrombosis and Hemostasis and Johannes Gutenberg University Medical Center, Mainz, Germany.|Third Medical Department, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Claudine
authors.initials: C
authors.lastname: Graf
authors.affiliation: Coagulation Biology Laboratory, Oklahoma Medical Research Foundation and Departments of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.affiliation: Center for Thrombosis and Hemostasis and Johannes Gutenberg University Medical Center, Mainz, Germany.|Department of Immunology and Microbial Science, the Scripps Research Institute, La Jolla, California.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018180:Thrombomodulin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D009569:Nitric Oxide
keywords: CXCL12/CXCR4; HSC mobilization; aPC/EPCR/PAR1 signaling; bone marrow retention; hematopoietic stem cells; nitric oxide; thrombomodulin