Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin ?v?3.

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 ?v?3 on HSCs. The resultant ?3 integrin outside-in signaling is dependent on thrombopoietin (TPO), a crucial cytokine involved in HSC maintenance. TPO was required for Nov binding to integrin ?v?3, and stimulated Nov expression in HSCs. However, in the presence of IFN?, 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 ?v?3 with exogenous ligands, including Nov, as well. Thus, Nov/integrin ?v?3-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.

SUBMITTER: Ishihara J 

PROVIDER: S-EPMC4412171 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature