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.
authors: Immunology Department, Weizmann Institute of Science, Rehovot, Israel;
authors: Anna
authors: A
authors: Aronovich
authors: Yaniv
authors: Y
authors: Nur
authors: Elias
authors: E
authors: Shezen
authors: Chava
authors: C
authors: Rosen
authors: Yael
authors: Y
authors: Zlotnikov Klionsky
authors: Irit
authors: I
authors: Milman
authors: Liran
authors: L
authors: Yarimi
authors: David
authors: D
authors: Hagin
authors: Gidi
authors: G
authors: Rechavi
authors: Uriel
authors: U
authors: Martinowitz
authors: Takashi
authors: T
authors: Nagasawa
authors: Paul S
authors: PS
authors: Frenette
authors: Dalit
authors: D
authors: Tchorsh-Yutsis
authors: Yair
authors: Y
authors: Reisner
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000502:physiology*; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D013917:Thrombin / Q000378:metabolism / Q000502:physiology*; D055114:X-Ray Microtomography
chemical_list: D044463:Receptor, PAR-1; D016179:Granulocyte Colony-Stimulating Factor; D005169:Factor VIII; D013917:Thrombin
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