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
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013
Y1 - 2013
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84891550694&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-08-447458
DO - 10.1182/blood-2012-08-447458
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AN - SCOPUS:84891550694
SN - 0006-4971
VL - 122
SP - 2562
EP - 2571
JO - Blood
JF - Blood
IS - 15
ER -