Journal
NATURE
Volume 486, Issue 7404, Pages 490-U87Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11163
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Funding
- National Institutes of Health [CA103866, CA129105, 1F32AG032833-01A1]
- Koch Institute
- Ellison Medical Foundation
- Warshaw Institute from the Massachusetts General Hospital
- Center for the study of Inflammatory Bowel Disease from the Massachusetts General Hospital
- NCI [T32CA09216]
- Academy of Finland
- Foundations' Post Doc Pool
- Jane Coffin Childs Medical Fund
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How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells-an ectoenzyme that produces the paracrine factor cyclic ADP ribose-mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.
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