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

15 Citations (Scopus)

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 CD34(low) 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
StatePublished - Oct 10 2013

Fingerprint

PAR-1 Receptor
Hematopoiesis
Factor VIII
Hematopoietic Stem Cells
Stem cells
Thrombin
Bone
Bone and Bones
Knockout Mice
Stem Cell Factor
Granulocyte Colony-Stimulating Factor
Coagulation
Bone Marrow
Tibia
Tomography
Maintenance
Tissue
Phenotype

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Aronovich, A., Nur, Y., Shezen, E., Rosen, C., Zlotnikov Klionsky, Y., Milman, I., ... 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.

A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. / Aronovich, Anna; Nur, Yaniv; Shezen, Elias; Rosen, Chava; Zlotnikov Klionsky, Yael; Milman, Irit; Yarimi, Liran; Hagin, David; Rechavi, Gidi; Martinowitz, Uriel; Nagasawa, Takashi; Frenette, Paul S.; Tchorsh-Yutsis, Dalit; Reisner, Yair.

In: Blood, Vol. 122, No. 15, 10.10.2013, p. 2562-2571.

Research output: Contribution to journalArticle

Aronovich, A, Nur, Y, Shezen, E, Rosen, C, Zlotnikov Klionsky, Y, Milman, I, Yarimi, L, Hagin, D, Rechavi, G, Martinowitz, U, Nagasawa, T, Frenette, PS, 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, vol. 122, no. 15, pp. 2562-2571.
Aronovich A, Nur Y, Shezen E, Rosen C, Zlotnikov Klionsky Y, Milman I et al. A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. Blood. 2013 Oct 10;122(15):2562-2571.
Aronovich, Anna ; Nur, Yaniv ; Shezen, Elias ; Rosen, Chava ; Zlotnikov Klionsky, Yael ; Milman, Irit ; Yarimi, Liran ; Hagin, David ; Rechavi, Gidi ; Martinowitz, Uriel ; Nagasawa, Takashi ; Frenette, Paul S. ; Tchorsh-Yutsis, Dalit ; Reisner, Yair. / A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. In: Blood. 2013 ; Vol. 122, No. 15. pp. 2562-2571.
@article{da20abbbe0b34419b8e4b0367937bc30,
title = "A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure.",
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 CD34(low) 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.",
author = "Anna Aronovich and Yaniv Nur and Elias Shezen and Chava Rosen and {Zlotnikov Klionsky}, Yael and Irit Milman and Liran Yarimi and David Hagin and Gidi Rechavi and Uriel Martinowitz and Takashi Nagasawa and Frenette, {Paul S.} and Dalit Tchorsh-Yutsis and Yair Reisner",
year = "2013",
month = "10",
day = "10",
language = "English (US)",
volume = "122",
pages = "2562--2571",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "15",

}

TY - JOUR

T1 - A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure.

AU - Aronovich, Anna

AU - Nur, Yaniv

AU - Shezen, Elias

AU - Rosen, Chava

AU - Zlotnikov Klionsky, Yael

AU - Milman, Irit

AU - Yarimi, Liran

AU - Hagin, David

AU - Rechavi, Gidi

AU - Martinowitz, Uriel

AU - Nagasawa, Takashi

AU - Frenette, Paul S.

AU - Tchorsh-Yutsis, Dalit

AU - Reisner, Yair

PY - 2013/10/10

Y1 - 2013/10/10

N2 - 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 CD34(low) 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.

AB - 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 CD34(low) 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.

UR - http://www.scopus.com/inward/record.url?scp=84891550694&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891550694&partnerID=8YFLogxK

M3 - Article

VL - 122

SP - 2562

EP - 2571

JO - Blood

JF - Blood

SN - 0006-4971

IS - 15

ER -