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

Jarom Heijmans; Jooske F. Van Lidth de Jeude; Bon Kyoung Koo; Sanne L. Rosekrans; Mattheus C.B. Wielenga; Marc Van De Wetering; Marc Ferrante; Amy S. Lee; Jos J.M. Onderwater; James C. Paton; Adrienne W. Paton; A. Mieke Mommaas; Liudmila L. Kodach; James C. Hardwick; Daniël W. Hommes; Hans Clevers; Vanesa Muncan; Gijs R. Van Den Brink

doi:10.1016/j.celrep.2013.02.031

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

Jarom Heijmans, Jooske F. Van Lidth de Jeude, Bon Kyoung Koo, Sanne L. Rosekrans, Mattheus C.B. Wielenga, Marc Van De Wetering, Marc Ferrante, Amy S. Lee, Jos J.M. Onderwater, James C. Paton, Adrienne W. Paton, A. Mieke Mommaas, Liudmila L. Kodach, James C. Hardwick, Daniël W. Hommes, Hans Clevers, Vanesa Muncan, Gijs R. Van Den Brink

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Abstract

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-eIF2α-dependent manner. Inhibition of Perk-eIF2α 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.

Original language	English
Pages (from-to)	1128-1139
Number of pages	12
Journal	Cell Reports
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2013.02.031
Publication status	Published - 25 Apr 2013
Externally published	Yes

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10.1016/j.celrep.2013.02.031

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Heijmans, J., Van Lidth de Jeude, J. F., Koo, B. K., Rosekrans, S. L., Wielenga, M. C. B., Van De Wetering, M., Ferrante, M., Lee, A. S., Onderwater, J. J. M., Paton, J. C., Paton, A. W., Mommaas, A. M., Kodach, L. L., Hardwick, J. C., Hommes, D. W., Clevers, H., Muncan, V., & Van Den Brink, G. R. (2013). ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response. Cell Reports, 3(4), 1128-1139. https://doi.org/10.1016/j.celrep.2013.02.031

@article{773e1010919b4612a3b7c329e3073ff2,

title = "ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response",

abstract = "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-eIF2α-dependent manner. Inhibition of Perk-eIF2α 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.",

author = "Jarom Heijmans and {Van Lidth de Jeude}, {Jooske F.} and Koo, {Bon Kyoung} and Rosekrans, {Sanne L.} and Wielenga, {Mattheus C.B.} and {Van De Wetering}, Marc and Marc Ferrante and Lee, {Amy S.} and Onderwater, {Jos J.M.} and Paton, {James C.} and Paton, {Adrienne W.} and Mommaas, {A. Mieke} and Kodach, {Liudmila L.} and Hardwick, {James C.} and Hommes, {Dani{\"e}l W.} and Hans Clevers and Vanesa Muncan and {Van Den Brink}, {Gijs R.}",

note = "Funding Information: The research leading to these results has received funding from the European Research Council under the European Community{\textquoteright}s Seventh Framework Program (FP7/2007-2013)/European Research Council grant agreement number 241344 (GvdB) and a VIDI grant from the Netherlands Organization for Scientific Research (GvdB). ",

year = "2013",

month = apr,

day = "25",

doi = "10.1016/j.celrep.2013.02.031",

language = "English",

volume = "3",

pages = "1128--1139",

journal = "Cell Reports",

issn = "2211-1247",

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Heijmans, J, Van Lidth de Jeude, JF, Koo, BK, Rosekrans, SL, Wielenga, MCB, Van De Wetering, M, Ferrante, M, Lee, AS, Onderwater, JJM, Paton, JC, Paton, AW, Mommaas, AM, Kodach, LL, Hardwick, JC, Hommes, DW, Clevers, H, Muncan, V & Van Den Brink, GR 2013, 'ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response', Cell Reports, vol. 3, no. 4, pp. 1128-1139. https://doi.org/10.1016/j.celrep.2013.02.031

TY - JOUR

T1 - ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response

AU - Heijmans, Jarom

AU - Van Lidth de Jeude, Jooske F.

AU - Koo, Bon Kyoung

AU - Rosekrans, Sanne L.

AU - Wielenga, Mattheus C.B.

AU - Van De Wetering, Marc

AU - Ferrante, Marc

AU - Lee, Amy S.

AU - Onderwater, Jos J.M.

AU - Paton, James C.

AU - Paton, Adrienne W.

AU - Mommaas, A. Mieke

AU - Kodach, Liudmila L.

AU - Hardwick, James C.

AU - Hommes, Daniël W.

AU - Clevers, Hans

AU - Muncan, Vanesa

AU - Van Den Brink, Gijs R.

N1 - Funding Information: The research leading to these results has received funding from the European Research Council under the European Community’s Seventh Framework Program (FP7/2007-2013)/European Research Council grant agreement number 241344 (GvdB) and a VIDI grant from the Netherlands Organization for Scientific Research (GvdB).

PY - 2013/4/25

Y1 - 2013/4/25

N2 - 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-eIF2α-dependent manner. Inhibition of Perk-eIF2α 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.

AB - 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-eIF2α-dependent manner. Inhibition of Perk-eIF2α 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.

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U2 - 10.1016/j.celrep.2013.02.031

DO - 10.1016/j.celrep.2013.02.031

M3 - Article

C2 - 23545496

AN - SCOPUS:84876998128

SN - 2211-1247

VL - 3

SP - 1128

EP - 1139

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

Abstract

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