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TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation

During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on natural products and antioxidants have shown very limited effects in alleviating de...

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Autores principales: Chen, Fei, Zhang, Yushuo, Hu, Songling, Shi, Xiaolin, Wang, Zhongmin, Deng, Zicheng, Lin, Longxin, Zhang, Jianghong, Pan, Yan, Bai, Yang, Liu, Fenju, Zhang, Haowen, Shao, Chunlin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338449/
https://www.ncbi.nlm.nih.gov/pubmed/32632140
http://dx.doi.org/10.1038/s41419-020-2715-6
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author Chen, Fei
Zhang, Yushuo
Hu, Songling
Shi, Xiaolin
Wang, Zhongmin
Deng, Zicheng
Lin, Longxin
Zhang, Jianghong
Pan, Yan
Bai, Yang
Liu, Fenju
Zhang, Haowen
Shao, Chunlin
author_facet Chen, Fei
Zhang, Yushuo
Hu, Songling
Shi, Xiaolin
Wang, Zhongmin
Deng, Zicheng
Lin, Longxin
Zhang, Jianghong
Pan, Yan
Bai, Yang
Liu, Fenju
Zhang, Haowen
Shao, Chunlin
author_sort Chen, Fei
collection PubMed
description During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on natural products and antioxidants have shown very limited effects in alleviating deadly GIS. Reserve intestinal stem cells (ISCs) and secretory progenitor cells are both reported to replenish damaged cells and contribute to crypt regeneration. However, the suppressed β-catenin/c-MYC axis within these slow-cycling cells leads to limited regenerative response to restore intestinal integrity during fatal accidental injury. Current study demonstrates that post-IR overexpression of TIGAR, a critical downstream target of c-MYC in mouse intestine, mounts a hyperplastic response in Bmi1-creERT(+) reserve ISCs, and thus rescues mice from lethal IR exposure. Critically, by eliminating damaging reactive oxygen species (ROS) yet retaining the proliferative ROS signals, TIGAR-overexpression enhances the activity of activator protein 1, which is indispensable for initiating reserve-ISC division after lethal radiation. In addition, it is identified that TIGAR-induction exclusively gears the Lgr5(−) subpopulation of reserve ISCs to regenerate crypts, and intestinal TIGAR-overexpression displays equivalent intestinal reconstruction to reserve-ISC-restricted TIGAR-induction. Our findings imply that precise administrations toward Lgr5(−) reserve ISCs are promising strategies for unpredictable lethal injury, and TIGAR can be employed as a therapeutic target for unexpected radiation-induced GIS.
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spelling pubmed-73384492020-07-09 TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation Chen, Fei Zhang, Yushuo Hu, Songling Shi, Xiaolin Wang, Zhongmin Deng, Zicheng Lin, Longxin Zhang, Jianghong Pan, Yan Bai, Yang Liu, Fenju Zhang, Haowen Shao, Chunlin Cell Death Dis Article During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on natural products and antioxidants have shown very limited effects in alleviating deadly GIS. Reserve intestinal stem cells (ISCs) and secretory progenitor cells are both reported to replenish damaged cells and contribute to crypt regeneration. However, the suppressed β-catenin/c-MYC axis within these slow-cycling cells leads to limited regenerative response to restore intestinal integrity during fatal accidental injury. Current study demonstrates that post-IR overexpression of TIGAR, a critical downstream target of c-MYC in mouse intestine, mounts a hyperplastic response in Bmi1-creERT(+) reserve ISCs, and thus rescues mice from lethal IR exposure. Critically, by eliminating damaging reactive oxygen species (ROS) yet retaining the proliferative ROS signals, TIGAR-overexpression enhances the activity of activator protein 1, which is indispensable for initiating reserve-ISC division after lethal radiation. In addition, it is identified that TIGAR-induction exclusively gears the Lgr5(−) subpopulation of reserve ISCs to regenerate crypts, and intestinal TIGAR-overexpression displays equivalent intestinal reconstruction to reserve-ISC-restricted TIGAR-induction. Our findings imply that precise administrations toward Lgr5(−) reserve ISCs are promising strategies for unpredictable lethal injury, and TIGAR can be employed as a therapeutic target for unexpected radiation-induced GIS. Nature Publishing Group UK 2020-07-06 /pmc/articles/PMC7338449/ /pubmed/32632140 http://dx.doi.org/10.1038/s41419-020-2715-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Fei
Zhang, Yushuo
Hu, Songling
Shi, Xiaolin
Wang, Zhongmin
Deng, Zicheng
Lin, Longxin
Zhang, Jianghong
Pan, Yan
Bai, Yang
Liu, Fenju
Zhang, Haowen
Shao, Chunlin
TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title_full TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title_fullStr TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title_full_unstemmed TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title_short TIGAR/AP-1 axis accelerates the division of Lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
title_sort tigar/ap-1 axis accelerates the division of lgr5(−) reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338449/
https://www.ncbi.nlm.nih.gov/pubmed/32632140
http://dx.doi.org/10.1038/s41419-020-2715-6
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