title: Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ3.
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.
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishihara
authors.forename: Terumasa
authors.initials: T
authors.lastname: Umemoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamato
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shiratsuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.forename: Brian G
authors.initials: BG
authors.lastname: Petrich
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013926:Thrombopoietin / Q000494:pharmacology
chemical_list: D039302:Integrin alphaVbeta3; D055514:Nephroblastoma Overexpressed Protein; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D013926:Thrombopoietin