Theranostics 2020; 10(22):10171-10185. doi:10.7150/thno.46415 This issue Cite

Research Paper

Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation

Sihan Wang1,3, Yi Han1,3, Jing Zhang2,3, Shu Yang1,3, Zeng Fan1, Feiling Song2,3, Lijuan He1,3, Wen Yue1,3, Yanhua Li2,3✉, Xuetao Pei1,3✉

1. Stem Cells and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China.
2. Experimental Hematology and Biochemistry Lab, Beijing Institute of Radiation Medicine, Beijing 100850, China.
3. South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China.

Citation:
Wang S, Han Y, Zhang J, Yang S, Fan Z, Song F, He L, Yue W, Li Y, Pei X. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics 2020; 10(22):10171-10185. doi:10.7150/thno.46415. https://www.thno.org/v10p10171.htm
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Abstract

Graphic abstract

Background: Acute gastrointestinal syndrome (AGS) is one of the most severe clinical manifestations after exposure to high doses of radiation, and is life-threatening in radiological emergency scenarios. However, an unmet challenge is lacking of an FDA-approved drug that can ameliorate the damage of radiation-exposed intestinal tissues and accelerate the regeneration of injured epithelia. In this study, we investigated whether the small molecule Me6TREN (Me6) can regulate intestinal stem cell (ISC) proliferation and promote crypt regeneration after irradiation.

Methods: Lethally irradiated mice were administered with Me6 or PBS to study the survival rate, and sections of their small intestine were subjected to immunostaining to evaluate epithelial regeneration. An intestinal organoid culture system was employed to detect the role of Me6 in organoid growth and ISC proliferation. We further investigated the key signaling pathways associated with Me6 using microarray, western blotting, and RNA interference techniques.

Results: We identified the small molecule Me6 as a potent intestinal radiation countermeasure. Systemic administration of Me6 significantly improved ISC and crypt cell regeneration and enhanced the survival of mice after high doses of radiation. Using an in vitro intestinal organoid culture system, we found that Me6 not only induced ISC proliferation but also increased the budding rate of intestinal organoids under unirradiated and irradiated conditions. Me6 remarkably activated the expression of ISC-associated and proliferation-promoting genes, such as Ascl2, Lgr5, Myc, and CyclinD1. Mechanistically, Me6 strongly stimulated the phosphorylation of β-catenin at the S552 site and increased the transcriptional activity of β-catenin, a key signaling pathway for ISC self-renewal and proliferation. This is further evidenced by the fact that knockdown of β-catenin abolished the effect of Me6 on intestinal organoid growth in vitro and crypt regeneration in irradiated mice.

Conclusion: The small molecule Me6TREN induced ISC proliferation, enhanced intestinal organoid growth in vitro, and promoted intestinal tissue regeneration after radiation injury by activating β-catenin signaling.

Keywords: Me6, Intestinal stem cell, Regeneration, Organoid, β-catenin


Citation styles

APA
Wang, S., Han, Y., Zhang, J., Yang, S., Fan, Z., Song, F., He, L., Yue, W., Li, Y., Pei, X. (2020). Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics, 10(22), 10171-10185. https://doi.org/10.7150/thno.46415.

ACS
Wang, S.; Han, Y.; Zhang, J.; Yang, S.; Fan, Z.; Song, F.; He, L.; Yue, W.; Li, Y.; Pei, X. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics 2020, 10 (22), 10171-10185. DOI: 10.7150/thno.46415.

NLM
Wang S, Han Y, Zhang J, Yang S, Fan Z, Song F, He L, Yue W, Li Y, Pei X. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics 2020; 10(22):10171-10185. doi:10.7150/thno.46415. https://www.thno.org/v10p10171.htm

CSE
Wang S, Han Y, Zhang J, Yang S, Fan Z, Song F, He L, Yue W, Li Y, Pei X. 2020. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics. 10(22):10171-10185.

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