mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.
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.
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Ömer H
ÖH
Yilmaz
Pekka
P
Katajisto
Dudley W
DW
Lamming
Yetis
Y
Gültekin
Khristian E
KE
Bauer-Rowe
Shomit
S
Sengupta
Kivanc
K
Birsoy
Abdulmetin
A
Dursun
V Onur
VO
Yilmaz
Martin
M
Selig
G Petur
GP
Nielsen
Mari
M
Mino-Kenudson
Lawrence R
LR
Zukerberg
Atul K
AK
Bhan
Vikram
V
Deshpande
David M
DM
Sabatini
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D031204:Caloric Restriction; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D002149:Energy Intake / Q000502:physiology*; D005260:Female; D058851:GPI-Linked Proteins / Q000819:agonists / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D008136:Longevity / Q000502:physiology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D019879:Paneth Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019899:Paracrine Communication; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D036563:Cyclic ADP-Ribose; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2; D020123:Sirolimus