Tissue Eng Regen Med.  2023 Aug;20(5):739-751. 10.1007/s13770-023-00541-0.

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/b-Catenin Pathway

• Yang L
• Fang C
• Song C
• Zhang Y
• Zhang R
• Zhou S

• KMID: 2545054
• DOI: http://doi.org/10.1007/s13770-023-00541-0

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-a 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/b-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 b-catenin pathways.

Keyword

Radiation enteritis; Mesenchymal stem cells; Exosomes; Lgr5; miR-195