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Updated: Jun 10, 2025
Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells MSCs
Published on: December 24, 2015
Intracellular osteopontin potentiates the immunosuppressive activity of mesenchymal stromal cells
Wanlin Yang1,2, Min Jin1,3, Yuting Gu1,3
1Department of Gastrointestinal Surgery, The Affiliated Changshu Hospital of Nantong University, Changshu, China.
Introduction:
Mesenchymal stromal cell (MSC)-based cell therapy is a promising approach for various inflammatory disorders based on their immunosuppressive capacity. Osteopontin (OPN) regulates several cellular functions including tissue repair, bone metabolism and immune reaction. However, the biological function of OPN in regulating the immunosuppressive capacity of MSCs remains elusive.
Objectives:
This study aims to highlight the underlying mechanism of the proinflammatory cytokines affect the therapeutic ability of MSCs through OPN.
Methods:
MSCs in response to the proinflammatory cytokines were collected to determine the expression profile of OPN. In vitro T-cell proliferation assays and gene editing were performed to check the role and mechanisms of OPN in regulating the immunosuppressive capacity of MSCs. Inflammatory disease mouse models were established to evaluate the effect of OPN on improving MSC-based immunotherapy.
Results:
We observed that OPN, including its two isoforms iOPN and sOPN, was downregulated in MSCs upon proinflammatory cytokine stimulation. Interestingly, iOPN, but not sOPN, greatly enhanced the immunosuppressive activity of MSCs on T-cell proliferation and thus alleviated the inflammatory pathologies of hepatitis and colitis. Mechanistically, iOPN interacted with STAT1 and mediated its deubiquitination, thereby inducing the master immunosuppressive mediator inducible nitric oxide synthase (iNOS) in MSCs. In addition, iOPN expression was directly downregulated by activated STAT1, which formed a negative feedback loop to restrain MSC immunosuppressive capacity.
Conclusion:
Our findings demonstrated that iOPN expression modulation in MSCs is a novel strategy to improve MSC-based immunotherapy.
Insights
Osteopontin (OPN) isoforms regulate mesenchymal stromal cell (MSC) immunosuppression. Intracellular OPN (iOPN) enhances MSC therapy for inflammatory diseases by boosting T-cell suppression via iNOS induction.
Area of Science:
- Immunology
- Cell Biology
- Biomedical Science
Background:
- Mesenchymal stromal cells (MSCs) show therapeutic potential for inflammatory disorders due to their immunosuppressive properties.
- Osteopontin (OPN) influences immune responses, but its role in MSC immunosuppression is unclear.
- Understanding OPN's function in MSCs could enhance cell-based immunotherapies.
Purpose of the Study:
- To elucidate the mechanism by which proinflammatory cytokines impact MSC therapeutic efficacy via OPN.
- To investigate the specific roles of OPN isoforms in regulating MSC immunosuppressive capacity.
Main Methods:
- Analyzed OPN expression in MSCs stimulated with proinflammatory cytokines.
- Utilized in vitro T-cell proliferation assays and gene editing to assess OPN's function.
- Employed inflammatory disease mouse models to evaluate OPN's impact on MSC-based immunotherapy.
Main Results:
- Proinflammatory cytokines downregulated OPN, including intracellular OPN (iOPN) and soluble OPN (sOPN), in MSCs.
- iOPN, but not sOPN, significantly augmented MSC immunosuppression of T-cell proliferation and ameliorated hepatitis and colitis.
- iOPN enhanced MSC immunosuppression by interacting with STAT1, promoting deubiquitination and inducing inducible nitric oxide synthase (iNOS).
Conclusions:
- iOPN plays a critical role in enhancing MSC immunosuppressive function.
- Modulating iOPN expression in MSCs presents a novel strategy for improving cell-based immunotherapy.
- STAT1-mediated negative feedback regulates iOPN and MSC immunosuppressive capacity.
