Nov/CCN3 regulates long-term repopulating activity of murine hematopoietic stem cells via integrin αvβ3
Open accessAbstract
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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IFN-g mainly affects the self-renewal and repopulating capacity of hematopoietic progenitors by moderating their response to other cytokines, mediated by STAT1 and SOCS1 and SOCS3.
“IFN-g mainly affects the self-renewal and repopulating capacity of hematopoietic progenitors by moderating their response to other cytokines.23 This effect is mainly mediated by STAT1 and suppressor of cytokine signaling 1 (SOCS1) and SOCS3 as effector molecules.21,24”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [23]
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- Authors
- Ishihara, J., Umemoto, T., Yamato, M., Shiratsuchi, Y., Takaki, S., Petrich, B. G., Nakauchi, H., Eto, K., Kitamura, T., & Okano, T.
- Affiliations
- Tokyo Women's Medical University (JP)
- University of California San Diego (US)
- Institute of Medical Science, The University of Tokyo (JP)
- Kyoto University (JP)
- Corresponding author
- Yamato, Masayuki
- ORCID
- Venue
- International Journal of Hematology
- Published
- 2014-02-22
- Volume
- 99
- Issue
- 4
- Pages
- 393-406
- ISSN
- 0925-5710 (ISSN-L)
- 1865-3774
- PMC
- PMC4412171
- OpenAlex
- W2142129883
- Cited by
- 28
- References
- 33
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 1
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- International Journal of Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (24300160, 25293097, 13J00246, 23249051, 22118001)
- National Heart, Lung, and Blood Institute (R01HL117061)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- hematopoietic stem cells, integrin αvβ3, thrombopoietin, bone marrow microenvironment, matricellular proteins, interferon-gamma, outside-in signaling, HSC maintenance
- MeSH terms
- Animals, Cell Differentiation, Hematopoietic Stem Cells, Interferon-gamma, Thrombopoietin, Signal Transduction, Gene Expression, Hematopoietic Stem Cell Transplantation, Integrin alphaVbeta3, STAT1 Transcription Factor, Mice, Nephroblastoma Overexpressed Protein
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