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

Nature Medicine volume 21, pages 1307–1317 (2015)Cite this article

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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 NOlow 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.

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Figure 1: Thrombin-PAR1 signaling induces HSC recruitment.
Figure 2: Thrombin-PAR1–dependent EPCR shedding induces HSC mobilization.
Figure 3: A bone marrow endothelial microenvironment enriched with TM and aPC regulates EPCR+ HSC retention.
Figure 4: aPC-EPCR-PAR1 signaling retains HSCs by inducing Cdc42 polarity and stabilizing VLA4.
Figure 5: Thrombin-PAR1 signaling induces NO production and HSC mobilization.
Figure 6: aPC-EPCR signaling limits NO production and promotes LT-HSC retention.

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  • 18 November 2015

    In the version of this article initially published, the first author's name was incorrect. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

Procrlow mice were provided by F.J. Castellino (University of Notre Dame). F2r−/− and F2rl2−/− were provided by P. Andrade-Gordon (Johnson & Johnson). ThbdPro/Pro mice were provided by H. Weiler (Blood Center of Wisconsin). Anti-TACE prodomain antibody was provided by C. Blobel (Hospital of Special Surgery). We thank C.E. Dunbar (NIH) for critically reviewing this manuscript and R. Rotkopf (Weizmann Institute of Science) for assistance in data statistical analysis. This study was supported by the Israel Science Foundation (851/13), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine and FP7-HEALTH-2010 (CELL-PID 261387) (T.L.) and NIH grants HL-31950, HL-60742, BMBF 01EO1003 and the Humboldt Foundation (W.R.).

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Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Shiri Gur-Cohen, Tomer Itkin, Orit Kollet, Aya Ludin, Karin Golan, Alexander Kalinkovich, Guy Ledergor, Elisabeth Niemeyer & Tsvee Lapidot

  2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Sagarika Chakrabarty & Wolfram Ruf

  3. Center for Thrombosis and Hemostasis, Johannes Gutenberg-University Medical Center, Mainz, Germany

    Claudine Graf & Wolfram Ruf

  4. Internal Medicine Department T, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Guy Ledergor

  5. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Eitan Wong, Ayelet Erez & Irit Sagi

  6. Universitätsklinikum Schleswig-Holstein Campus Luebeck, Klinik für Strahlentherapie, Universitaet zu Luebeck, Germany

    Elisabeth Niemeyer

  7. Department of Biological Services, Flow Cytometry Unit, Weizmann Institute of Science, Rehovot, Israel

    Ziv Porat

  8. Oklahoma Medical Research Foundation and Departments of Pathology and Biochemistry & Molecular Biology, Coagulation Biology Laboratory, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Charles T Esmon

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  1. Shiri Gur-Cohen
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Contributions

S.G.C. designed and performed experiments, analyzed data and wrote the manuscript; T.I. helped design and execute experiments and analyzed data; S.C. performed experiments and analyzed data; C.G. performed experiments; A.L., O.K., K.G., A.K., G.L. and E.N. helped with experiments; Z.P. helped with imaging flow cytometry; E.W. and I.S. provided help and guidance in experiments related to TACE prodomain inhibitor and EPCR shedding mechanism; A.E. helped design eNOS and NO-related experiments; C.T.E. provided help and guidance in EPCR- and TACE-related experiments; W.R. designed experiments and wrote the manuscript; T.L. designed the research and wrote the manuscript.

Corresponding authors

Correspondence to Wolfram Ruf or Tsvee Lapidot.

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Gur-Cohen, S., Itkin, T., Chakrabarty, S. et al. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med 21, 1307–1317 (2015). https://doi.org/10.1038/nm.3960

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