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

被引：40

作者：

Aronovich, Anna ^{[1
]}

Nur, Yaniv ^{[1
]}

Shezen, Elias ^{[1
]}

Rosen, Chava ^{[1
]}

Klionsky, Yael Zlotnikov ^{[1
]}

Milman, Irit ^{[1
]}

Yarimi, Liran ^{[1
]}

Hagin, David ^{[1
]}

Rechavi, Gidi ^{[2
]}

Martinowitz, Uriel ^{[3
]}

Nagasawa, Takashi ^{[4
,5
]}

Frenette, Paul S. ^{[6
]}

Tchorsh-Yutsis, Dalit ^{[1
]}

Reisner, Yair ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel

[2] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel

[3] Chaim Sheba Med Ctr, Israel Natl Hemophilia Ctr, IL-52621 Tel Hashomer, Israel

[4] Kyoto Univ, Inst Frontier, Dept Immunobiol & Hematol, Kyoto, Japan

[5] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Tokyo, Japan

[6] Albert Einstein Coll Med, Inst Stem Cell & Regenerat Med, Bronx, NY 10467 USA

来源：

BLOOD | 2013年 / 122卷 / 15期

关键词：

PROTEASE-ACTIVATED RECEPTOR-1; STEM-CELL NICHE; PROGENITOR CELLS; C RECEPTOR; SPLEEN TRANSPLANTATION; SIZE CONTROL; ORGAN SIZE; HEMOPHILIA; MARROW; MICE;

D O I：

10.1182/blood-2012-08-447458

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：2562 / 2571

页数：10

共 41 条

[1]

Correction of hemophilia as a proof of concept for treatment of monogenic diseases by fetal spleen transplantation [J].