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

被引：572

作者：

Yilmaz, Oemer H. ^{[1
,2
,3
,4
,5
,6
,7
]}

Katajisto, Pekka ^{[1
,4
,5
,6
,7
]}

Lamming, Dudley W. ^{[1
,4
,5
,6
,7
]}

Gueltekin, Yetis ^{[1
,2
,3
,4
,5
,6
,7
]}

Bauer-Rowe, Khristian E. ^{[1
,4
,5
,6
,7
]}

Sengupta, Shomit ^{[1
,4
,5
,6
,7
]}

Birsoy, Kivanc ^{[1
,4
,5
,6
,7
]}

Dursun, Abdulmetin ^{[2
,3
]}

Yilmaz, V. Onur ^{[1
,4
,5
,6
,7
]}

Selig, Martin ^{[2
,3
]}

Nielsen, G. Petur ^{[2
,3
]}

Mino-Kenudson, Mari ^{[2
,3
]}

Zukerberg, Lawrence R. ^{[2
,3
]}

Bhan, Atul K. ^{[2
,3
]}

Deshpande, Vikram ^{[2
,3
]}

Sabatini, David M. ^{[1
,4
,5
,6
,7
]}

机构：

[1] Whitehead Inst Biomed Res, Boston, MA 02142 USA

[2] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA 02114 USA

[4] MIT, Dept Biol, Cambridge, MA 02139 USA

[5] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[6] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA

[7] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

来源：

NATURE | 2012年 / 486卷 / 7404期

基金：

美国国家卫生研究院; 芬兰科学院;

关键词：

DIETARY RESTRICTION; MICE; HOMEOSTASIS; PTEN; LGR5; RENEWAL; C57BL/6; IMPACT; GROWTH; SIZE;

D O I：

10.1038/nature11163

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：490 / U87

页数：8

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