Journal
HEMATOPOIETIC STEM CELLS IX
Volume 1370, Issue -, Pages 65-81Publisher
BLACKWELL SCIENCE PUBL
DOI: 10.1111/nyas.13013
Keywords
hematopoietic stem cells; HSC mobilization; bone marrow retention; aPC/EPCR/PAR1 signaling; thrombomodulin; CXCL12/CXCR4; nitric oxide
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Funding
- Israel Science Foundation [851/13]
- Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine
- FP7-HEALTH [CELL-PID 261387]
- Weizmann-University of Michigan-Technion Collaboration Program
- NIH [HL-60742]
- Humboldt Foundation
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The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adultmurine bonemarrow (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 NOlow 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.
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