A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure

Anna Aronovich, Yaniv Nur, Elias Shezen, Chava Rosen, Yael Zlotnikov Klionsky, Irit Milman, Liran Yarimi, David Hagin, Gidi Rechavi, Uriel Martinowitz, Takashi Nagasawa, Paul S. Frenette, Dalit Tchorsh-Yutsis, Yair Reisner

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Analysis of hematopoietic stem cells (HSCs) in factor VIII knockout (FVIIIKO) mice revealed a novel regulatory role for the coagulation cascade in hematopoiesis. Thus, HSCs in FVIIIKO mice had reduced proportions of CD34low cells within Lin-Sca+Kit+ progenitors, and exhibited reduced long-term repopulating capacity as well as hyper granulocyte–colony-stimulating factor (G-CSF)–induced mobilization. This disregulation of HSCs is likely caused by reduced levels of thrombin, and is associated with altered protease-activated receptor 1 (PAR1) signaling, as PAR1 KO mice also exhibited enhanced G-CSF–induced mobilization. Analysis of reciprocal bone marrow (BM) chimera (FVIIIKO BM into wild-type recipients and vice versa) and the detection of PAR1 expression on stromal elements indicates that this phenotype is likely controlled by stromal elements. Micro–computed tomography analysis of distal tibia metaphyses also revealed for the first time a major impact of the FVIII/thrombin/PAR1 axis on the dynamic bone structure, showing reduced bone:tissue volume ratio and trabecular number in FVIIIKO and PAR1KO mice. Taken together, these results show a critical and novel role for the coagulation cascade, mediated in part by thrombin-PAR1 interaction, and regulates HSC maintenance and a reciprocal interplay between HSCs and the dynamic bone structure.

Original languageEnglish (US)
Pages (from-to)2562-2571
Number of pages10
JournalBlood
Volume122
Issue number15
DOIs
StatePublished - Jan 1 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Aronovich, A., Nur, Y., Shezen, E., Rosen, C., Zlotnikov Klionsky, Y., Milman, I., Yarimi, L., Hagin, D., Rechavi, G., Martinowitz, U., Nagasawa, T., Frenette, P. S., Tchorsh-Yutsis, D., & Reisner, Y. (2013). A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. Blood, 122(15), 2562-2571. https://doi.org/10.1182/blood-2012-08-447458