Publication Date:
2012-06-23
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387287/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yilmaz, Omer H -- Katajisto, Pekka -- Lamming, Dudley W -- Gultekin, 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 -- 1F32AG032833-01A1/AG/NIA NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- F32 AG032833/AG/NIA NIH HHS/ -- P30 AG038072/AG/NIA NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- T32CA09216/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 28;486(7404):490-5. doi: 10.1038/nature11163.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722868" target="_blank"〉PubMed〈/a〉
Keywords:
ADP-ribosyl Cyclase/metabolism
;
Animals
;
Antigens, CD/metabolism
;
Caloric Restriction
;
Cell Count
;
Cell Division/drug effects
;
Cyclic ADP-Ribose/metabolism
;
Energy Intake/*physiology
;
Female
;
GPI-Linked Proteins/agonists/metabolism
;
Intestines/*cytology
;
Longevity/physiology
;
Male
;
Mice
;
Multiprotein Complexes
;
Paneth Cells/*cytology/drug effects/*metabolism
;
Paracrine Communication
;
Proteins/antagonists & inhibitors/*metabolism
;
Regeneration/drug effects
;
Signal Transduction
;
Sirolimus/pharmacology
;
Stem Cell Niche/drug effects/*physiology
;
Stem Cells/*cytology/drug effects/*metabolism
;
TOR Serine-Threonine Kinases
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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