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Extravascular coagulation in hematopoietic stem and progenitor cell regulation

T. Son Nguyen, Tsvee Lapidot and Wolfram Ruf

Abstract

The hemostatic system plays pivotal roles in injury repair, innate immunity and adaptation to inflammatory challenges. We here review the evidence that these vascular protective mechanisms have non-traditional roles in hematopoietic stem cell (HSC) maintenance in their physiological bone marrow (BM) niches at steady state and under stress. Expression of coagulation factors and the extrinsic coagulation initiator tissue factor by osteoblasts, tissue resident macrophages and megakaryocytes suggests that endosteal as well as vascular HSC niches are functionally regulated by extravascular coagulation. The anticoagulant endothelial protein C receptor (EPCR, Procr) is highly expressed by primitive BM HSC and endothelial cells. EPCR is associated with its major ligand activated protein C (aPC) in proximity to thrombomodulin (TM)+ blood vessels, enforcing HSC integrin α4 adhesion and chemotherapy resistance in the context of CXCL12-CXCR4 niche retention signals. Protease-activated receptor 1 biased signaling by EPCR-aPC also maintains HSC retention, whereas thrombin signaling activates HSC motility and bone marrow egress. HSC mobilization under stress is furthermore enhanced by the fibrinolytic and complement cascades which target HSC and their BM niches. Furthermore, coagulation, fibrinolysis and HSC-derived progeny, including megakaryocytes, synergize to re-establish functional perivascular HSC niches during BM stress. Therapeutic restoration of the anticoagulant pathway has preclinical efficacy in reversing bone marrow failure following radiation injury, but open questions remain on how antithrombotic therapy influences extravascular coagulation in HSC maintenance and hematopoiesis.

  • Submitted December 6, 2017.
  • Accepted February 5, 2018.