Non-enzymatic role of SOD1 in intestinal stem cell growth
Abstract Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestin...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05267-w |
| _version_ | 1811336440933515264 |
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| author | Ying-Chao Wang Xiao-Xu Leng Cheng-Bei Zhou Shi-Yuan Lu Chi Kwan Tsang Jie Xu Ming-Ming Zhang Hui-Min Chen Jing-Yuan Fang |
| author_facet | Ying-Chao Wang Xiao-Xu Leng Cheng-Bei Zhou Shi-Yuan Lu Chi Kwan Tsang Jie Xu Ming-Ming Zhang Hui-Min Chen Jing-Yuan Fang |
| author_sort | Ying-Chao Wang |
| collection | DOAJ |
| description | Abstract Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen–inducible intestinal epithelial cell–specific Sod1 knockout (Sod1 f/f ; Vil-creERT2) mice. We found that loss of Sod1 in organoids suppressed the proliferation and survival of cells and Lgr5 gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive Sod1 mutants could completely rescue the growth defects of Sod1 deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover, Sod1 deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in Sod1 deficient organoids. In vivo, epithelial Sod1 loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for Sod1 loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis. |
| first_indexed | 2024-04-13T17:39:30Z |
| format | Article |
| id | doaj.art-3dab9c9d621a4a2997306fc5d81240e3 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T17:39:30Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-3dab9c9d621a4a2997306fc5d81240e32022-12-22T02:37:13ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011310.1038/s41419-022-05267-wNon-enzymatic role of SOD1 in intestinal stem cell growthYing-Chao Wang0Xiao-Xu Leng1Cheng-Bei Zhou2Shi-Yuan Lu3Chi Kwan Tsang4Jie Xu5Ming-Ming Zhang6Hui-Min Chen7Jing-Yuan Fang8Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityClinical Neuroscience Institute, The First Affiliated Hospital of Jinan UniversityInstitutes of Biomedical Sciences, Zhongshan-Xuhui Hospital, Fudan UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen–inducible intestinal epithelial cell–specific Sod1 knockout (Sod1 f/f ; Vil-creERT2) mice. We found that loss of Sod1 in organoids suppressed the proliferation and survival of cells and Lgr5 gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive Sod1 mutants could completely rescue the growth defects of Sod1 deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover, Sod1 deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in Sod1 deficient organoids. In vivo, epithelial Sod1 loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for Sod1 loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis.https://doi.org/10.1038/s41419-022-05267-w |
| spellingShingle | Ying-Chao Wang Xiao-Xu Leng Cheng-Bei Zhou Shi-Yuan Lu Chi Kwan Tsang Jie Xu Ming-Ming Zhang Hui-Min Chen Jing-Yuan Fang Non-enzymatic role of SOD1 in intestinal stem cell growth Cell Death and Disease |
| title | Non-enzymatic role of SOD1 in intestinal stem cell growth |
| title_full | Non-enzymatic role of SOD1 in intestinal stem cell growth |
| title_fullStr | Non-enzymatic role of SOD1 in intestinal stem cell growth |
| title_full_unstemmed | Non-enzymatic role of SOD1 in intestinal stem cell growth |
| title_short | Non-enzymatic role of SOD1 in intestinal stem cell growth |
| title_sort | non enzymatic role of sod1 in intestinal stem cell growth |
| url | https://doi.org/10.1038/s41419-022-05267-w |
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