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Mesenchymal Stem Cells Promote Intestinal Mucosal Repair by Positively Regulating the Nrf2/Keap1/ARE Signaling Pathway in Acute Experimental Colitis

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Abstract

Background/Aims

Mesenchymal stem cells (MSCs) are a type of adult pluripotent stem cell that has anti-inflammatory and immunomodulatory effects, and whose conditioned medium (CM) has also been found to be effective. We used MSC and CM enemas to investigate their ameliorative effects in a mouse model of colitis.

Methods

We employed MSCs, CM, and MSCs + ML385 (an inhibitor of Nrf2) in dextran sodium sulfate (DSS)-induced colitis. Mice were sacrificed on day 8, and the effects of MSC or CM treatment on the levels of inflammation and oxidative stress in colonic epithelial cells were evaluated by histological analyses.

Results

MSCs inhibited inflammatory cell infiltration and proinflammatory cytokine expression in the colon. In addition, MSCs reduced extracellular matrix deposition and maintained the mechanical barrier and permeability of colonic epithelial cells. Mechanistically, MSCs activated Nrf2, which then increased HO-1 and NQO-1 levels and downregulated the expression of Keap1 to suppress reactive oxygen species production and MDA generation, accompanied by increases in components of the enzymatic antioxidant system, including SOD, CAT, GSH-Px, and T-AOC. However, after administering an Nrf2 inhibitor (ML385) to block the Nrf2/Keap1/ARE pathway, we failed to observe protective effects of MSCs in mice with colitis. CM alone also produced some of the therapeutic benefits of MSCs but was not as effective as MSCs.

Conclusions

Our data confirmed that MSCs and CM can effectively improve intestinal mucosal repair in experimental colitis and that MSCs can improve this condition by activating the Nrf2/Keap1/ARE pathway.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgments

We thank Dr. Canxia Xu at The Third Xiangya Hospital of Central South University for the critical comments to the manuscript.

Funding

This work received support from Independent Exploration and Innovation project for postgraduate of Central South University (grant no. 2021zzts0406), National Natural Science Foundation of China (grant no. 81570509), and Changsha Municipal Natural Science Foundation (grant no. kq2014257).

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Author notes

  1. Can-xia Xu

    Present address: Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China

Authors and Affiliations

  1. Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China

    Peng Liu, Xiao-ran Xie, Hao Wu, Huan Li, Jing-shu Chi, Xiao-ming Liu, Ju Luo & Yu Tang

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Contributions

L.P., X.X.R., W.H., C.J.S., and L.H. conceived and designed the study, conducted the experiments, interpreted the data, and prepared the manuscript. L.X.M., T.Y., and L.J. take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final article.

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Correspondence to Peng Liu.

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Supplementary Information

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10620_2022_7722_MOESM1_ESM.jpg

Supplementary file1 (JPG 1117 KB) Supplementary Fig. 1. Distribution of GFP+ MSCs in colon 2 day after treatment. A GFP was transfected to MSC, and the GFP-labeling was confirmed. B GFP + cells were detected at the inflamed colon. On the fourth day of the mouse model of colitis, both healthy mice and colitis mice were anal injected with GFP + MSCs (1 × 106, 200 μL in volume). In the control group, no cells clustered in the intestinal mucosa; In the DSS-modeling group, cells were found accumulation at the lumen. Magnification: × 40. Scale bar, 100 μm

10620_2022_7722_MOESM2_ESM.jpg

Supplementary file1 (JPG 2933 KB) Supplementary Fig. 2. Therapeutic effects of untreated culture medium (UCM) in DSS-induced colitis mice. A Representative colon images and quantification of colon length. B Distal colons were removed and sectioned followed by H&E staining. Representative sections are displayed. Inflammation scores were evaluated in bar graph. C IHC analysis for the macrophage specific marker CD68 was performed and subsequently positive cells were evaluated. D IHC analysis for the neutrophil specific marker MPO was performed and subsequently positive cells were evaluated. The insets are magnified images of the indicated rectangles. Magnification: × 100. Scale bar, 200 μm. Values are the means ± SD. n = 6 animals per group per time point. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001; ns no significance

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Liu, P., Xie, Xr., Wu, H. et al. Mesenchymal Stem Cells Promote Intestinal Mucosal Repair by Positively Regulating the Nrf2/Keap1/ARE Signaling Pathway in Acute Experimental Colitis. Dig Dis Sci 68, 1835–1846 (2023). https://doi.org/10.1007/s10620-022-07722-2

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