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Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver

September 26th, 2023
Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver
Animal experiment grouping and timeline. Detailed descriptions are provided in the Materials and Methods. In brief, we established short-term and long-term liver ischemia-reperfusion mouse models to explore the therapeutic potential of menstrual blood-derived stromal cells (MenSCs) and primed MenSCs. MenSCs: Menstrual blood-derived stromal cells; IFN-γ: Interferon-γ; 1MT: 1-methyl-D-tryptophan; IR: Ischemia-reperfusion; IRM: Combination treated with ischemia-reperfusion and menstrual blood-derived stromal cells; IRM (IFN-γ): Combination treated with ischemia-reperfusion and interferon-γ-primed menstrual blood-derived stromal cells; PBS: Phosphate buffered saline; i.v.: Intravenous injection. Credit: World Journal of Stem Cells (2023). DOI: 10.4252/wjsc.v15.i9.876

Mesenchymal stem cells (MSCs) have been used in liver transplantation and have certain effects in alleviating liver ischemia-reperfusion injury (IRI) and regulating immune rejection. However, some studies have indicated that the effects of MSCs are not very significant. Therefore, approaches that enable MSCs to exert significant and stable therapeutic effects are worth further study.

Aim

To enhance the therapeutic potential of human menstrual blood-derived stromal cells (MenSCs) in the mouse liver ischemia-reperfusion (I/R) model via interferon-γ (IFN-γ) priming.

Methods

Apoptosis was analyzed by flow cytometry to evaluate the safety of IFN-γ priming, and indoleamine 2,3-dioxygenase (IDO) levels were measured by quantitative real-time reverse transcription polymerase chain reaction, western blotting, and ELISA to evaluate the efficacy of IFN-γ priming.

In vivo, the liver I/R model was established in male C57/BL mice, hematoxylin and eosin and TUNEL staining was performed and serum liver enzyme levels were measured to assess the degree of liver injury, and regulatory T cell (Treg) numbers in spleens were determined by flow cytometry to assess immune tolerance potential.

Metabolomics analysis was conducted to elucidate the potential mechanism underlying the regulatory effects of primed MenSCs. In vitro, we established a hypoxia/reoxygenation (H/R) model and analyzed apoptosis by flow cytometry to investigate the mechanism through which primed MenSCs inhibit apoptosis. Transmission electron microscopy, western blotting, and immunofluorescence were used to analyze autophagy levels.

Results

IFN-γ-primed MenSCs secreted higher levels of IDO, attenuated liver injury, and increased Treg numbers in the mouse spleens to greater degrees than untreated MenSCs. Metabolomics and autophagy analyses proved that primed MenSCs more strongly induced autophagy in the mouse livers. In the H/R model, autophagy inhibitors increased the level of H/R-induced apoptosis, indicating that autophagy exerted protective effects.

In addition, primed MenSCs decreased the level of H/R-induced apoptosis via IDO and autophagy. Further rescue experiments proved that IDO enhanced the protective autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway and activating the AMPK pathway.

Conclusion

IFN-γ-primed MenSCs exerted better therapeutic effects in the liver I/R model by secreting higher IDO levels. MenSCs and IDO activated the AMPK-mTOR-autophagy axis to reduce IRI, and IDO increased Treg numbers in the spleen and enhanced the MenSC-mediated induction of immune tolerance. Our study suggests that IFN-γ-primed MenSCs may be a novel and superior MSC product for liver transplantation in the future.

The paper is published in the World Journal of Stem Cells.

More information:
Qi Zhang et al, Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver ischemia-reperfusion model, World Journal of Stem Cells (2023). DOI: 10.4252/wjsc.v15.i9.876

Provided by World Journal of Stem Cells

Citation: Interferon-γ priming enhances the therapeutic effects of menstrual blood-derived stromal cells in a mouse liver (2023, September 26) retrieved 18 May 2024 from https://sciencex.com/wire-news/457189541/interferon-priming-enhances-the-therapeutic-effects-of-menstrua.html
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