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Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn’s disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an esse...

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Autores principales: Bao, Weilian, You, Yan, Ni, Jiahui, Hou, Hui, Lyu, Jiaren, Feng, Guize, Wang, Yirui, You, Keyuan, Zhang, Sulin, Zhang, Lijie, Cao, Xinyue, Wang, Xu, Li, Haidong, Li, Hong, Xu, Jiake, Liu, Chenying, Luo, Xiaomin, Du, Peng, Chen, Daofeng, Shen, Xiaoyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468130/
https://www.ncbi.nlm.nih.gov/pubmed/37647408
http://dx.doi.org/10.1126/sciadv.adh5016
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author Bao, Weilian
You, Yan
Ni, Jiahui
Hou, Hui
Lyu, Jiaren
Feng, Guize
Wang, Yirui
You, Keyuan
Zhang, Sulin
Zhang, Lijie
Cao, Xinyue
Wang, Xu
Li, Haidong
Li, Hong
Xu, Jiake
Liu, Chenying
Luo, Xiaomin
Du, Peng
Chen, Daofeng
Shen, Xiaoyan
author_facet Bao, Weilian
You, Yan
Ni, Jiahui
Hou, Hui
Lyu, Jiaren
Feng, Guize
Wang, Yirui
You, Keyuan
Zhang, Sulin
Zhang, Lijie
Cao, Xinyue
Wang, Xu
Li, Haidong
Li, Hong
Xu, Jiake
Liu, Chenying
Luo, Xiaomin
Du, Peng
Chen, Daofeng
Shen, Xiaoyan
author_sort Bao, Weilian
collection PubMed
description Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn’s disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.
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spelling pubmed-104681302023-08-31 Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells Bao, Weilian You, Yan Ni, Jiahui Hou, Hui Lyu, Jiaren Feng, Guize Wang, Yirui You, Keyuan Zhang, Sulin Zhang, Lijie Cao, Xinyue Wang, Xu Li, Haidong Li, Hong Xu, Jiake Liu, Chenying Luo, Xiaomin Du, Peng Chen, Daofeng Shen, Xiaoyan Sci Adv Biomedicine and Life Sciences Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn’s disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs. American Association for the Advancement of Science 2023-08-30 /pmc/articles/PMC10468130/ /pubmed/37647408 http://dx.doi.org/10.1126/sciadv.adh5016 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Bao, Weilian
You, Yan
Ni, Jiahui
Hou, Hui
Lyu, Jiaren
Feng, Guize
Wang, Yirui
You, Keyuan
Zhang, Sulin
Zhang, Lijie
Cao, Xinyue
Wang, Xu
Li, Haidong
Li, Hong
Xu, Jiake
Liu, Chenying
Luo, Xiaomin
Du, Peng
Chen, Daofeng
Shen, Xiaoyan
Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title_full Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title_fullStr Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title_full_unstemmed Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title_short Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells
title_sort inhibiting sorting nexin 10 promotes mucosal healing through srebp2-mediated stemness restoration of intestinal stem cells
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468130/
https://www.ncbi.nlm.nih.gov/pubmed/37647408
http://dx.doi.org/10.1126/sciadv.adh5016
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