mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

• Published in: Nature (London) Vol. 486; no. 7404; pp. 490 - 495
• Main Authors: Yilmaz, Ömer H., Katajisto, Pekka, Lamming, Dudley W., Gültekin, Yetis, Bauer-Rowe, Khristian E., Sengupta, Shomit, Birsoy, Kivanc, Dursun, Abdulmetin, Yilmaz, V. Onur, Selig, Martin, Nielsen, G. Petur, Mino-Kenudson, Mari, Zukerberg, Lawrence R., Bhan, Atul K., Deshpande, Vikram, Sabatini, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2012; Nature Publishing Group
• Subjects: 631/136/532/2139; 631/80/83/2359; ADP-ribosyl Cyclase - metabolism; Aging; Animals; Antigens, CD - metabolism; Caloric Restriction; Cancer; Cell Count; Cell Division - drug effects; Cellular control mechanisms; Cyclic ADP-Ribose - metabolism; Diet; Energy Intake - physiology; Female; GPI-Linked Proteins - agonists; GPI-Linked Proteins - metabolism; Health aspects; Humanities and Social Sciences; Intestine, Small; Intestines - cytology; Longevity - physiology; Low-calorie diet; Male; Mammals; Mechanistic Target of Rapamycin Complex 1; Mice; multidisciplinary; Multiprotein Complexes; Paneth Cells - cytology; Paneth Cells - drug effects; Paneth Cells - metabolism; Paracrine Communication; Physiological aspects; Protein kinases; Proteins - antagonists & inhibitors; Proteins - metabolism; Regeneration - drug effects; Rodents; Science; Science (multidisciplinary); Signal Transduction; Sirolimus - pharmacology; Stem Cell Niche - drug effects; Stem Cell Niche - physiology; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; TOR Serine-Threonine Kinases; Weight control; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11163

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. In the mouse intestine, calorie restriction enhances the regenerative capacity of intestinal stem cells by reducing mTORC1 signalling in their Paneth cell niche. Calorie restriction and the gut Reducing caloric intake while maintaining adequate nutrition extends lifespan in diverse organisms, possibly by preserving stem- and progenitor-cell function. David Sabatini and colleagues show that in the mouse intestine, caloric restriction leads to an increased number of intestinal stem cells (ISC) with enhanced regenerative capacity. The effects are mediated by modulation of mTOR signalling in Paneth cells, important components of the ISC niche. Caloric restriction leads to the expression of the Bst1 gene in Paneth cells and subsequent secretion of cyclic ADP ribose, which acts on ISCs in a paracrine manner. These findings demonstrate a link between the stem-cell function and the nutritional status of an organism, and raise the possibility that mTORC1 inhibitors or Bst1 mimetics may have therapeutic application in improving intestinal regeneration and function.