Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells
| Autor: | Maryam Yousefi, Angela Nakauka-Ddamba, Corbett T. Berry, Ning Li, Jenna Schoenberger, Devon Bankler-Jukes, Kamen P. Simeonov, Ryan J. Cedeno, Zhengquan Yu, Christopher J. Lengner |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Calorie restriction reserve intestinal stem cells mTORC1 Nutrient sensing Biology Mechanistic Target of Rapamycin Complex 1 Biochemistry 03 medical and health sciences Mice Report Genetics Animals Homeostasis Intestinal Mucosa lcsh:QH301-705.5 intestine mTORC1 signaling Tissue homeostasis Cell Proliferation lcsh:R5-920 Regeneration (biology) Stem Cells Cell Biology calorie restriction Intestinal epithelium Cell biology Intestines Mice Inbred C57BL 030104 developmental biology lcsh:Biology (General) radiosensitivity regeneration Stem cell biological phenomena cell phenomena and immunity lcsh:Medicine (General) Adult stem cell Developmental Biology DNA Damage radiation injury |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 10, Iss 3, Pp 703-711 (2018) |
| ISSN: | 2213-6711 |
| Popis: | Summary Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool. Cell-autonomous activity of mechanistic target of rapamycin complex 1 (mTORC1) governs the sensitivity of reserve ISCs to injury. CR inhibits mTORC1 in these cells, protecting them against DNA damage, while mTORC1 stimulation, either genetically or through nutrient sensing, sensitizes reserve ISCs to injury, thus compromising regeneration of the epithelium. These data delineate a critical role for mTORC1 in epithelial regeneration and inform clinical strategies based on nutrient modulation. Graphical Abstract Highlights • Calorie restriction increases the radioresistant intestinal stem cell (ISC) pool • Calorie restriction suppresses mTORC1 activity in reserve ISCs • Reserve ISC-autonomous mTORC1 activity governs ISC survival post injury • Calorie-restricted reserve ISCs have enhanced regenerative capacity post injury In this study, Yousefi et al. identify reserve intestinal stem cell-autonomous suppression of mTORC1 activity in response to calorie restriction as the basis for enhanced regeneration of the intestinal epithelium after DNA-damaging injury. Conversely, the authors demonstrate that acute nutrient-based stimulation of mTORC1 prior to injury results in reserve stem cell apoptosis and intestinal regenerative failure. |
| Databáze: | OpenAIRE |
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