Insulin-like Growth Factor-1 and mTORC1 Signaling Promote the Intestinal Regenerative Response After Irradiation Injury
| Autor: | Natacha Bohin, Kelley S. Yan, Elizabeth A. Carlson, Linda C. Samuelson, Kevin P. McGowan, Theresa M. Keeley |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Intestinal Repair EDU 5-ethynyl-2´-deoxyuridine mTORC1 Mice 0302 clinical medicine Insulin-Like Growth Factor I Intestinal Mucosa ANOVA analysis of variance Original Research DPI days post-irradiation FSC facultative stem cell Stem Cells Gastroenterology qPCR quantitative reverse transcriptase polymerase chain reaction mTORC1 mammalian target of rapamycin complex 1 Intestinal epithelium Cell biology Raptor Intestines Intestinal Stem Cells Radiation Injuries Experimental Editorial HPI hours post-irradiation ISC intestinal stem cell IGF-1 030211 gastroenterology & hepatology Stem cell Crypt Regeneration UNIRR unirradiated controls Signal Transduction Crypt PBS phosphate-buffered saline IGF-1 insulin-like growth factor-1 Biology Mechanistic Target of Rapamycin Complex 1 SEM standard error of the mean 03 medical and health sciences medicine Animals Regeneration Rapamycin Progenitor cell lcsh:RC799-869 Hepatology Growth factor Regeneration (biology) Mesenchymal stem cell 030104 developmental biology Gamma Rays lcsh:Diseases of the digestive system. Gastroenterology CBC crypt base columnar |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 4, Pp 797-810 (2020) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Intestinal crypts have a remarkable capacity to regenerate after injury from loss of crypt base columnar (CBC) stem cells. After injury, facultative stem cells (FSCs) are activated to replenish the epithelium and replace lost CBCs. Our aim was to assess the role of insulin-like growth factor-1 (IGF-1) to activate FSCs for crypt repair. Methods The intestinal regenerative response was measured after whole body 12-Gy γ-irradiation of adult mice. IGF-1 signaling or its downstream effector mammalian target of rapamycin complex 1 (mTORC1) was inhibited by administering BMS-754807 or rapamycin, respectively. Mice with inducible Rptor gene deletion were studied to test the role of mTORC1 signaling in the intestinal epithelium. FSC activation post-irradiation was measured by lineage tracing. Results We observed a coordinate increase in growth factor expression, including IGF-1, at 2 days post-irradiation, followed by a surge in mTORC1 activity during the regenerative phase of crypt repair at day 4. IGF-1 was localized to pericryptal mesenchymal cells, and IGF-1 receptor was broadly expressed in crypt progenitor cells. Inhibition of IGF-1 signaling via BMS-754807 treatment impaired crypt regeneration after 12-Gy irradiation, with no effect on homeostasis. Similarly, rapamycin inhibition of mTORC1 during the growth factor surge blunted the regenerative response. Analysis of Villin-CreERT2;Rptorfl/fl mice showed that epithelial mTORC1 signaling was essential for crypt regeneration. Lineage tracing from Bmi1-marked cells showed that rapamycin blocked FSC activation post-irradiation. Conclusions Our study shows that IGF-1 signaling through mTORC1 drives crypt regeneration. We propose that IGF-1 release from pericryptal cells stimulates mTORC1 in FSCs to regenerate lost CBCs. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|