Cell death & disease, 2020-07, Vol.11 (7), p.501-501, Article 501
2020
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- Autor(en) / Beteiligte
- Titel
- TIGAR/AP-1 axis accelerates the division of Lgr5− reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation
- Ist Teil von
- Cell death & disease, 2020-07, Vol.11 (7), p.501-501, Article 501
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-4889eISSN: 2041-4889DOI: 10.1038/s41419-020-2715-6Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7338449
- Format
- –
- Schlagworte
- 13/100, 13/106, 13/31, 13/44, 13/51, 14/19, 38/35, 631/532/2437, 64/110, 692/308/2171, Activator protein 1, Animals, Antibodies, Antioxidants, Apoptosis Regulatory Proteins - metabolism, Biochemistry, Biomedical and Life Sciences, c-Myc protein, Cell Biology, Cell Culture, Female, Gastrointestinal Diseases - etiology, Gastrointestinal Diseases - pathology, Immunology, Intestine, Intestines - cytology, Ionizing radiation, Life Sciences, Male, Mice, Models, Biological, Myc protein, Natural products, Phosphoric Monoester Hydrolases - metabolism, Progenitor cells, Radiation, Ionizing, Reactive oxygen species, Reactive Oxygen Species - metabolism, Receptors, G-Protein-Coupled - metabolism, Regeneration - radiation effects, Signal Transduction, Stem cell transplantation, Stem cells, Stem Cells - metabolism, Stem Cells - radiation effects, Therapeutic applications, Transcription Factor AP-1 - metabolism, Transcription factors, β-Catenin