ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response

被引：232

作者：

Heijmans, Jarom y ^{[1
,2
]}

de Jeude, Jooske F. van Lidth ^{[1
,2
]}

Koo, Bon-Kyoung

Rosekrans, Sanne L. ^{[1
,2
]}

Wielenga, Mattheus C. B. ^{[1
,2
]}

van de Wetering, Marc

Ferrante, Marc

Lee, Amy S. ^{[5
]}

Onderwater, Jos J. M. ^{[4
]}

Paton, James C. ^{[6
]}

Paton, Adrienne W. ^{[6
]}

Mommaas, A. Mieke ^{[4
]}

Kodach, Liudmila L. ^{[3
]}

Hardwick, James C. ^{[3
]}

Hommes, Daniel W. ^{[3
,7
]}

Clevers, Hans

Muncan, Vanesa ^{[1
,2
]}

van den Brink, Gijs R. ^{[1
,2
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Tytgat Inst Liver & Intestinal Res, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[3] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, NL-2333 ZA Leiden, Netherlands

[4] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Electron Microscopy Sect, NL-2333 ZA Leiden, Netherlands

[5] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA

[6] Univ Adelaide, Sch Mol & Biomed Sci, Res Ctr Infect Dis, Adelaide, SA 5005, Australia

[7] Univ Calif Los Angeles, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90095 USA

来源：

CELL REPORTS | 2013年 / 3卷 / 04期

基金：

欧洲研究理事会;

关键词：

GENE-EXPRESSION; CELLS; DEPHOSPHORYLATION; DELETION;

D O I：

10.1016/j.celrep.2013.02.031

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Stem cells generate rapidly dividing transit-amplifying cells that have lost the capacity for self-renewal but cycle for a number of times until they exit the cell cycle and undergo terminal differentiation. We know very little of the type of signals that trigger the earliest steps of stem cell differentiation and mediate a stem cell to transit-amplifying cell transition. We show that in normal intestinal epithelium, endoplasmic reticulum (ER) stress and activity of the unfolded protein response (UPR) are induced at the transition from stem cell to transit-amplifying cell. Induction of ER stress causes loss of stemness in a Perk-eIF2 alpha-dependent manner. Inhibition of Perk-eIF2 alpha signaling results in stem cell accumulation in organoid culture of primary intestinal epithelium. Our findings show that the UPR plays an important role in the regulation of intestinal epithelial stem cell differentiation.

引用

页码：1128 / 1139

页数：12

共 33 条

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Identification of stem cells in small intestine and colon by marker gene Lgr5 [J].