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

Nat Med. 2015 Nov;21(11):1307-17. doi: 10.1038/nm.3960. Epub 2015 Oct 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Bone Marrow / metabolism
  • Cell Adhesion
  • Cell Movement
  • Chemokine CXCL12 / metabolism
  • Endothelial Protein C Receptor
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Integrin alpha4beta1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism*
  • Protein C / metabolism*
  • Receptor, PAR-1 / metabolism*
  • Receptors, CXCR4 / metabolism
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Thrombin / metabolism*
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • CXCR4 protein, mouse
  • Cdc42 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Endothelial Protein C Receptor
  • Integrin alpha4beta1
  • Procr protein, mouse
  • Protein C
  • Receptor, PAR-1
  • Receptors, CXCR4
  • Receptors, Cell Surface
  • Nitric Oxide
  • Thrombin
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse
  • cdc42 GTP-Binding Protein