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, 10 (1), 368

Acetylsalicylic Acid Rescues the Immunomodulation of Inflamed Gingiva-Derived Mesenchymal Stem Cells via Upregulating FasL in Mice

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Acetylsalicylic Acid Rescues the Immunomodulation of Inflamed Gingiva-Derived Mesenchymal Stem Cells via Upregulating FasL in Mice

Tingting Yu et al. Stem Cell Res Ther.

Abstract

Background: Gingiva-derived mesenchymal stem cells (GMSCs) obtained multipotent differentiation and immunomodulatory properties. However, collecting healthy gingival tissues may be challenging in the clinical situation. Thus, in our present study, we aim to evaluate whether the immunomodulatory capacity of gingiva-derived mesenchymal stem cells from inflamed gingival tissues (iGMSCs) is impaired and find a way to rescue their deficient properties.

Methods: We compared the immunomodulation capacity of GMSCs and iGMSCs using an in vitro co-culture system and a mouse colitis model. T cell apoptosis, T helper 17 (Th17), and regulatory T (Treg) cell differentiation were detected by flow cytometry analysis.

Results: We demonstrated that iGMSCs obtained a decreased immunomodulatory capacity compared with GMSCs. Acetylsalicylic acid (ASA) pretreatment was able to rescue iGMSCs' impaired immunomodulatory properties. Mechanistically, ASA was capable of upregulating the expression of Fas ligand (FasL) in iGMSCs, leading to an improvement in iGMSC-mediated T cell apoptosis and therapeutic efficacy in the treatment in colitis mice.

Conclusions: This study indicates that the deficient immunomodulatory function of iGMSCs could be rescued by ASA pretreatment via upregulating of FasL in mice. This strategy might serve as a practical approach to rescue deficient MSC function for further therapeutic application.

Keywords: Cell therapy; Fas pathway; Immunomodulation; Mesenchymal stem cell.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
iGMSCs obtained impaired stemness compared with GMSCs. a Micro-CT showed significant alveolar bone resorption in ligature-induced periodontitis in mice. b iGMSCs exhibited reduced single colony-forming ability. c, d Flow cytometric analysis of the expression of Sca1, CD105, CD90, CD73, CD44, CD45, and CD34 in iGMSCs and GMSCs. e Continued culture assay showed that iGMSCs had less elevated population doubling than GMSCs. f BrdU+ labeling assay showed decreased proliferation rate in iGMSCs compared with GMSCs. n = 5 in each group. *P < 0.05. **P < 0.01. ***P < 0.005. Error bars: mean ± SD
Fig. 2
Fig. 2
The immunomodulatory properties of iGMSCs are impaired. a In vitro co-culture system showed a significantly decreased capacity of iGMSCs to induce Annexin V+/7AAD+ T cell apoptosis when compared with the GMSC group. b Schema showing iGMSC and GMSC transplantation for treating dextran sodium sulfate (DSS)-induced experimental colitis mice. ce iGMSCs showed impaired immunomodulation capacity compared with GMSCs, as assessed by c amelioration of losing body weight, d decreased disease activity index (DAI), and e alleviation of colitis histologic activity index (HAI). fh FACS analysis showed that the levels of Th1 and Th17 were significantly elevated while the levels of Tregs were significantly reduced in colitis mice compared with the control mice. iGMSC infusion exhibited compromised reduction of Th1 and Th17 cells and upregulation of Treg levels in colitis in mice than did GMSCs. i ELISA analysis showed that the levels of tumor necrosis factor α (TNF-α) and IL-17 in serum were markedly increased in colitis mice compared with the control mice at 10 days post-DSS induction. iGMSC infusion exhibited compromised ability to downregulate serum levels of TNF-α and IL-17 compared with GMSCs. n = 5 in each group. Scale bar = 200 μm. *P < 0.05. **P < 0.01. ***P < 0.005. Error bars: mean ± SD
Fig. 3
Fig. 3
ASA treatment rescues the impaired immunomodulatory properties of iGMSCs. a In vitro co-culture system showed a significantly increased capacity of ASA-treated iGMSCs to induce Annexin V+/7AAD+ T cell apoptosis when compared with the iGMSC group. b Western blot analysis showed that ASA treatment elevated the expression of FasL in iGMSCs. ce ASA-treated iGMSCs showed restored immunomodulation capacity compared with untreated iGMSCs, as assessed by c amelioration of losing body weight, d decreased disease activity index (DAI), and e alleviation of colitis histologic activity index (HAI). f FACS analysis showed that ASA-treated iGMSC infusion rescued the iGMSCs’ ability to reduce Th1 and Th17 cells and elevate Treg cells in colitis mice. g ELISA analysis showed that ASA-treated iGMSC infusion rescued the iGMSCs’ ability to downregulate the levels of TNF-α and IL-17 in colitis mice. n = 5 in each group. Scale bar = 200 μm. *P < 0.05. **P < 0.01. ***P < 0.005. Error bars: mean ± SD
Fig. 4
Fig. 4
ASA treatment rescues the impaired immunomodulation capacity of iGMSCs via upregulation of FasL. a Western blot analysis showed that FasL siRNA downregulated the expression level of FasL in ASA-iGMSCs. b, c In vitro co-culture system showed that FasL siRNA-treated ASA-iGMSCs was not able to sufficiently induce Annexin V+/7AAD+ T cell apoptosis compared with untreated ASA-iGMSCs. df FasL siRNA-treated ASA-iGMSCs showed decreased immunomodulation capacity compared with untreated ASA-iGMSCs, as assessed by d amelioration of losing body weight, e decreased disease activity index (DAI), and f alleviation of colitis histologic activity index (HAI). g FasL siRNA treatment inhibits ASA-iGMSCs’ ability to reduce the levels of Th1 and Th17 cells and elevate the levels of Treg cells in colitis mice. h FasL siRNA treatment inhibits ASA-iGMSCs’ ability to downregulate the serum levels of TNF-α and IL-17 in colitis mice. n = 5 in each group. Scale bar = 200 μm. *P < 0.05. **P < 0.01. ***P < 0.005. Error bars: mean ± SD

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