p53 promotes revival stem cells in the regenerating intestine after severe radiation injury
Abstract Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target gen...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47124-8 |
| _version_ | 1827264528150167552 |
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| author | Clara Morral Arshad Ayyaz Hsuan-Cheng Kuo Mardi Fink Ioannis I. Verginadis Andrea R. Daniel Danielle N. Burner Lucy M. Driver Sloane Satow Stephanie Hasapis Reem Ghinnagow Lixia Luo Yan Ma Laura D. Attardi Constantinos Koumenis Andy J. Minn Jeffrey L. Wrana Chang-Lung Lee David G. Kirsch |
| author_facet | Clara Morral Arshad Ayyaz Hsuan-Cheng Kuo Mardi Fink Ioannis I. Verginadis Andrea R. Daniel Danielle N. Burner Lucy M. Driver Sloane Satow Stephanie Hasapis Reem Ghinnagow Lixia Luo Yan Ma Laura D. Attardi Constantinos Koumenis Andy J. Minn Jeffrey L. Wrana Chang-Lung Lee David G. Kirsch |
| author_sort | Clara Morral |
| collection | DOAJ |
| description | Abstract Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. Together, our findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells. |
| first_indexed | 2024-04-24T09:52:46Z |
| format | Article |
| id | doaj.art-f8259dde53cf4c8bad036795c5ff982c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2025-03-22T03:47:29Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f8259dde53cf4c8bad036795c5ff982c2024-04-28T11:26:47ZengNature PortfolioNature Communications2041-17232024-04-0115111410.1038/s41467-024-47124-8p53 promotes revival stem cells in the regenerating intestine after severe radiation injuryClara Morral0Arshad Ayyaz1Hsuan-Cheng Kuo2Mardi Fink3Ioannis I. Verginadis4Andrea R. Daniel5Danielle N. Burner6Lucy M. Driver7Sloane Satow8Stephanie Hasapis9Reem Ghinnagow10Lixia Luo11Yan Ma12Laura D. Attardi13Constantinos Koumenis14Andy J. Minn15Jeffrey L. Wrana16Chang-Lung Lee17David G. Kirsch18Department of Radiation Oncology, Perelman School of Medicine, University of PennsylvaniaCentre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Pharmacology and Cancer Biology, Duke UniversityCentre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Radiation Oncology, Perelman School of Medicine, University of PennsylvaniaDepartment of Radiation Oncology, Duke UniversityDepartment of Pharmacology and Cancer Biology, Duke UniversityDepartment of Radiation Oncology, Duke UniversityDepartment of Radiation Oncology, Duke UniversityDepartment of Radiation Oncology, Duke UniversityDepartment of Radiation Oncology, Perelman School of Medicine, University of PennsylvaniaDepartment of Radiation Oncology, Duke UniversityDepartment of Radiation Oncology, Duke UniversityDepartments of Radiation Oncology and Genetics, Stanford UniversityDepartment of Radiation Oncology, Perelman School of Medicine, University of PennsylvaniaDepartment of Radiation Oncology, Perelman School of Medicine, University of PennsylvaniaCentre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Radiation Oncology, Duke UniversityDepartment of Pharmacology and Cancer Biology, Duke UniversityAbstract Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. Together, our findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells.https://doi.org/10.1038/s41467-024-47124-8 |
| spellingShingle | Clara Morral Arshad Ayyaz Hsuan-Cheng Kuo Mardi Fink Ioannis I. Verginadis Andrea R. Daniel Danielle N. Burner Lucy M. Driver Sloane Satow Stephanie Hasapis Reem Ghinnagow Lixia Luo Yan Ma Laura D. Attardi Constantinos Koumenis Andy J. Minn Jeffrey L. Wrana Chang-Lung Lee David G. Kirsch p53 promotes revival stem cells in the regenerating intestine after severe radiation injury Nature Communications |
| title | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| title_full | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| title_fullStr | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| title_full_unstemmed | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| title_short | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| title_sort | p53 promotes revival stem cells in the regenerating intestine after severe radiation injury |
| url | https://doi.org/10.1038/s41467-024-47124-8 |
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