Intrinsic Autophagy Is Required for the Maintenance of Intestinal Stem Cells and for Irradiation-Induced Intestinal Regeneration

被引：110

作者：

Asano, Jumpei ^{[1
]}

Sato, Taku ^{[1
,4
]}

Ichinose, Shizuko ^{[2
]}

Kajita, Mihoko ^{[1
]}

Onai, Nobuyuki ^{[1
]}

Shimizu, Shigeomi ^{[3
]}

Ohteki, Toshiaki ^{[1
]}

机构：

[1] TMDU, Dept Biodef Res, Med Res Inst, Tokyo 1138510, Japan

[2] TMDU, Res Ctr Med & Dent Sci, Tokyo 1138510, Japan

[3] TMDU, Dept Pathol Cell Biol, Med Res Inst, Tokyo 1138510, Japan

[4] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol PRESTO, Kawaguchi, Saitama 3320012, Japan

来源：

CELL REPORTS | 2017年 / 20卷 / 05期

基金：

日本科学技术振兴机构;

关键词：

GENOME-WIDE ASSOCIATION; CROHN-DISEASE; PANETH CELLS; MITOCHONDRIA; EXPRESSION; CRYPT; DIFFERENTIATION; IDENTIFICATION; ATG16L1; ABSENCE;

D O I：

10.1016/j.celrep.2017.07.019

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Autophagy is a lysosomal degradation pathway with important roles in physiological homeostasis and disease. However, the role of autophagy in intestinal stem cells (ISCs) is unclear. Here, we show that intrinsic autophagy in ISCs is important for ISC homeostasis. Mice lacking autophagy protein 5 (ATG5) in intestinal epithelial cells (iECs) (Villin-Cre: Atg5(fl/fl), hereafter Atg5(Delta IEC) mice) or in all iECs except Paneth cells (Ah-Cre: Atg5(fl/fl) mice) had significantly fewer ISCs than did control mice and showed impaired ISC-dependent intestinal recovery after irradiation. Crypt ISCs from Atg5(Delta IEC) mice had significantly higher reactive oxygen species (ROS) levels than did those from control mice. A ROS-inducing reagent decreased the ISC number and impaired ISC regenerative capacity ex vivo, and treating Atg5(Delta IEC) mice with an antioxidant rescued their defects. Our results show that intrinsic autophagy supports ISC maintenance by reducing excessive ROS. Optimizing autophagy may lead to autophagy-based therapies for intestinal injuries.

引用

页码：1050 / 1060

页数：11

共 50 条

[11] Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury [J].

Fordham, Robert P. ;

Yui, Shiro ;

Hannan, Nicholas R. F. ;

Soendergaard, Christoffer ;

Madgwick, Alison ;

Schweiger, Pawel J. ;

Nielsen, Ole H. ;

Vallier, Ludovic ;

Pedersen, Roger A. ;

Nakamura, Tetsuya ;

Watanabe, Mamoru ;

Jensen, Kim B. .

CELL STEM CELL, 2013, 13 (06) :734-744

[12] Autophagy maintains stemness by preventing senescence [J].

Garcia-Prat, Laura ;

Martinez-Vicente, Marta ;

Perdiguero, Eusebio ;

Ortet, Laura ;

Rodriguez-Ubreva, Javier ;

Rebollo, Elena ;

Ruiz-Bonilla, Vanessa ;

Gutarra, Susana ;

Ballestar, Esteban ;

Serrano, Antonio L. ;

Sandri, Marco ;

Munoz-Canoves, Pura .

NATURE, 2016, 529 (7584) :37-+

[13] N-acetylcysteine, coenzyme Q10 and superoxide dismutase mimetic prevent mitochondrial cell dysfunction and cell death induced by D-galactosamine in primary culture of human hepatocytes [J].

Gonzalez, Raul ;

Ferrin, Gustavo ;

Hidalgo, Ana B. ;

Ranchal, Isidora ;

Lopez-Cillero, Pedro ;

Santos-Gonzalez, Monica ;

Lopez-Lluch, Guillermo ;

Briceno, Javier ;

Gomez, Miguel A. ;

Poyato, Antonio ;

Villalba, Jose M. ;

Navas, Placido ;

de la Mata, Manuel ;

Muntane, Jordi .

CHEMICO-BIOLOGICAL INTERACTIONS, 2009, 181 (01) :95-106

[14] A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 [J].

Hampe, Jochen ;

Franke, Andre ;

Rosenstiel, Philip ;

Till, Andreas ;

Teuber, Markus ;

Huse, Klaus ;

Albrecht, Mario ;

Mayr, Gabriele ;

De La Vega, Francisco M. ;

Briggs, Jason ;

Guenther, Simone ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Haesler, Robert ;

Sipos, Bence ;

Foelsch, Ulrich R. ;

Lengauer, Thomas ;

Platzer, Matthias ;

Mathew, Christopher G. ;

Krawczak, Michael ;

Schreiber, Stefan .

NATURE GENETICS, 2007, 39 (02) :207-211

[15] ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response [J].

Heijmans, Jarom y ;

de Jeude, Jooske F. van Lidth ;

Koo, Bon-Kyoung ;

Rosekrans, Sanne L. ;

Wielenga, Mattheus C. B. ;

van de Wetering, Marc ;

Ferrante, Marc ;

Lee, Amy S. ;

Onderwater, Jos J. M. ;

Paton, James C. ;

Paton, Adrienne W. ;

Mommaas, A. Mieke ;

Kodach, Liudmila L. ;

Hardwick, James C. ;

Hommes, Daniel W. ;

Clevers, Hans ;

Muncan, Vanesa ;

van den Brink, Gijs R. .

CELL REPORTS, 2013, 3 (04) :1128-1139

[16] Starvation Compromises Paneth Cells [J].

Hodin, Caroline M. ;

Lenaerts, Kaatje ;

Grootjans, Joep ;

de Haan, Jacco J. ;

Hadfoune, M'hamed ;

Verheyen, Fons K. ;

Kiyama, Hiroshi ;

Heineman, Erik ;

Buurman, Wim A. .

AMERICAN JOURNAL OF PATHOLOGY, 2011, 179 (06) :2885-2893

[17] Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract:: Effect of loss of β-catenin [J].

Ireland, H ;

Kemp, R ;

Houghton, C ;

Howard, L ;

Clarke, AR ;

Sansom, OJ ;

Winton, DJ .

GASTROENTEROLOGY, 2004, 126 (05) :1236-1246

[18] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells [J].

Ito, K ;

Hirao, A ;

Arai, F ;

Takubo, K ;

Matsuoka, S ;

Miyamoto, K ;

Ohmura, M ;

Naka, K ;

Hosokawa, K ;

Ikeda, Y ;

Suda, T .

NATURE MEDICINE, 2006, 12 (04) :446-451

[19] Selective degradation of mitochondria by mitophagy [J].

Kim, Insil ;

Rodriguez-Enriquez, Sara ;

Lemasters, John J. .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2007, 462 (02) :245-253

[20] Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells [J].

Kim, Tae-Hee ;

Escudero, Silvia ;

Shivdasani, Ramesh A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (10) :3932-3937

← 1 2 3 4 5 →