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REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration

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Abstract

Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a marker of intestinal stem cells (ISCs), is considered to play key roles in tissue homoeostasis and regeneration after acute radiation injury. However, the activation of Lgr5 by integrated signaling pathways upon radiation remains poorly understood. Here, we show that irradiation of mice with whole-body depletion or conditional ablation of REGγ in Lgr5+ stem cell impairs proliferation of intestinal crypts, delaying regeneration of intestine epithelial cells. Mechanistically, REGγ enhances transcriptional activation of Lgr5 via the potentiation of both Wnt and Hippo signal pathways. TEAD4 alone or cooperates with TCF4, a transcription factor mediating Wnt signaling, to enhance the expression of Lgr5. Silencing TEAD4 drastically attenuated β-catenin/TCF4 dependent expression of Lgr5. Together, our study reveals how REGγ controls Lgr5 expression and expansion of Lgr5+ stem cells in the regeneration of intestinal epithelial cells. Thus, REGγ proteasome appears to be a potential therapeutic target for radiation-induced gastrointestinal disorders.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82073483, 31730017, 82022051), the Science and Technology Commission of Shanghai Municipality (19JC1411900, 20s11901500), Changning Maternity and Infant Health Hospital PI team building project (311–20031). We also thank ECNU Multifunctional Platform for Innovation (011) for keeping and raising mice.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, 20051, China

    Xiaotao Li

  2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Xiangzhan Zhu, Solomon Kibreab Mael, Lili Zhang, Yaqi Kong, Yuping Ren, Zimeng Wang, Ying Zhang, Bo Yang, Tingmei Huang, Lei Li, Xiaotao Li & Bianhong Zhang

  3. Department of Orthopedic Oncology, Changzheng Hospital, the Second Military Medical University, Shanghai, 200003, China

    Minglei Yang

  4. Department of Spinal Surgery, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, China

    Zaijun Lin

  5. Henan Key Laboratory for Helicobacter pylori & Microbiota and GI cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Ya Li

  6. Department of Neonatology, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China

    Xiangzhan Zhu & Yaodong Zhang

  7. Department of Pathology, Xuchang Central Hospital Affiliated to Henan University of Science and Technology, Xuchang, 461000, China

    Jianhui Li

  8. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China

    Fangxia Guan

  9. Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA

    Zhenlong Li

  10. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Robb E. Moses & Xiaotao Li

  11. Department of Oncological Surgery, Minhang Branch, Shanghai Cancer Center, Fudan University, Shanghai, 200240, China

    Bing Wang

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  1. Xiangzhan Zhu
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  2. Minglei Yang
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  19. Bing Wang
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  21. Bianhong Zhang
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Correspondence to Bing Wang, Xiaotao Li or Bianhong Zhang.

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Zhu, X., Yang, M., Lin, Z. et al. REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration. Sci. China Life Sci. 65, 1608–1623 (2022). https://doi.org/10.1007/s11427-021-2018-7

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  • DOI: https://doi.org/10.1007/s11427-021-2018-7

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