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01-04-2014 | Original Article

Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ3

Authors: Jun Ishihara, Terumasa Umemoto, Masayuki Yamato, Yoshiko Shiratsuchi, Satoshi Takaki, Brian G. Petrich, Hiromitsu Nakauchi, Koji Eto, Toshio Kitamura, Teruo Okano

Published in: International Journal of Hematology | Issue 4/2014

Abstract

Throughout life, hematopoietic stem cells (HSCs) sustain the blood cell supply through their capacities for self-renewal and multilineage differentiation. These processes are regulated within a specialized microenvironment termed the ‘niche’. Here, we show a novel mechanism for regulating HSC function that is mediated by nephroblastoma overexpressed (Nov/CCN3), a matricellular protein member of the CCN family. We found that Nov contributes to the maintenance of long-term repopulating (LTR) activity through association with integrin αvβ3 on HSCs. The resultant β3 integrin outside-in signaling is dependent on thrombopoietin (TPO), a crucial cytokine involved in HSC maintenance. TPO was required for Nov binding to integrin αvβ3, and stimulated Nov expression in HSCs. However, in the presence of IFNγ, a cytokine known to impair HSC function, not only was TPO-induced expression of Nov suppressed, but the LTR activity was conversely impaired by TPO-mediated ligation of integrin αvβ3 with exogenous ligands, including Nov, as well. Thus, Nov/integrin αvβ3-mediated maintenance of HSCs appears to be modulated by simultaneous stimulation by other cytokines. Our finding suggests that this system contributes to the regulation of HSCs within the bone marrow niche.

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Title: Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ3
Authors: Jun Ishihara
Terumasa Umemoto
Masayuki Yamato
Yoshiko Shiratsuchi
Satoshi Takaki
Brian G. Petrich
Hiromitsu Nakauchi
Koji Eto
Toshio Kitamura
Teruo Okano
Publication date: 01-04-2014
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 4/2014
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-014-1534-x

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