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Mesenchymal Stem Cell-Derived Exosomes are Effective for Radiation Enteritis and Essential for the Proliferation and Differentiation of Lgr5+ Intestinal Epithelial Stem Cells by Regulating Mir-195/Akt/β-Catenin Pathway

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Radiation enteritis (RE) is a common complication of abdominal or pelvic radiotherapy, which when severe, could be life-threatening. Currently, there are no effective treatments. Studies have shown that mesenchymal stem cells (MSCs)-derived exosomes (MSC-exos) exhibit promising therapeutic effects in inflammatory diseases. However, the specific role of MSC-exos in RE and the regulatory mechanisms remain elusive.

Methods:

In vivo assay was carried out by injecting MSC-exos into the total abdominal irradiation (TAI)-induced RE mouse model. For in vitro assay, Lgr5-positive intestinal epithelial stem cells (Lgr5+ IESC) were extracted from mice, followed by irradiation along with MSC-exos treatment. HE staining was performed to measure histopathological changes. mRNA expression of inflammatory factors TNF-α and IL-6 and stem cell markers LGR5, and OCT4 were quantified by RT-qPCR. EdU and TUNEL staining was performed to estimate cell proliferation and apoptosis. MiR-195 expression in TAI mice and radiation-induced Lgr5+ IESC was tested.

Results:

We found that the injection of MSC-exos inhibited inflammatory reaction, increased stem cell marker expression, and maintained intestinal epithelial integrity in TAI mice. Furthermore, MSC-exos treatment increased the proliferation and simultaneously suppressed apoptosis in radiation-stimulated Lgr5+ IESC. MiR-195 expression increased by radiation exposure was decreased by MSC-exos therapy. MiR-195 overexpression facilitated the progress of RE by counteracting the effect of MSC-exos. Mechanistically, the Akt and Wnt/β-catenin pathways inhibited by MSC-exos were activated by miR-195 upregulation.

Conclusion:

MSC-Exos are effective in treating RE and are essential for the proliferation and differentiation of Lgr5+ IESCs. Moreover, MSC-exos mediates its function by regulating miR-195 Akt β-catenin pathways.

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Acknowledgements

This work was supported by the Zhejiang Medical and Health Science and Technology Plan Project (No. 2022PY028), Zhejiang Medical and Health Youth Talents Project (No. 2019RC087), Science and Technology Department of Taizhou City (No. 20ywb30).

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  1. Leilei Yang and Chengfeng Fang are contributed equally to this work.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, No. 150, Ximen Street, Linhai, Taizhou, 317000, Zhejiang, China

    Leilei Yang, Chengfeng Fang, Caifang Song, Yaya Zhang, Ruili Zhang & Shenkang Zhou

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Contributions

LY, RZ, and SZ conceived and designed the experiments. LY, and CF contributed significantly to the experiments. LY, CF, and CS helped with the experiments and arranging data. CS and YZ performed the data analyses. YZ, and YZ helped perform the analysis with constructive discussions. LY and CF wrote the draft manuscript. RZ and SZ revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ruili Zhang or Shenkang Zhou.

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All the animal protocols were approved by the Ethics Committee of Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University (IACUC no. [2021]-034).

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Yang, L., Fang, C., Song, C. et al. Mesenchymal Stem Cell-Derived Exosomes are Effective for Radiation Enteritis and Essential for the Proliferation and Differentiation of Lgr5+ Intestinal Epithelial Stem Cells by Regulating Mir-195/Akt/β-Catenin Pathway. Tissue Eng Regen Med 20, 739–751 (2023). https://doi.org/10.1007/s13770-023-00541-0

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