ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response
Open accessAbstract
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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The UPR has been implicated in regulating the inflammatory response and stemness within the intestinal epithelium.
“the UPR has been implicated in regulating processes as diverse as the inflammatory response (609) and stemness within the intestinal epithelium (251).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [251]
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References 34 · Cited by 293
- Authors
- 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.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- University of Southern California (US)
- Leiden University Medical Center (NL)
- The University of Adelaide (AU)
- University of California, Los Angeles (US)
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 3
- Issue
- 4
- Pages
- 1128-1139
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2163899199
- Cited by
- 293
- References
- 34
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 27 · 2023: 18 · 2022: 18 · 2021: 27 · 2020: 30 · 2019: 30 · 2018: 18 · 2017: 18 · 2016: 21 · 2015: 18 · 2014: 22 · 2013: 4
- FWCI
- 12.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- endoplasmic reticulum stress, unfolded protein response, intestinal stem cells, stem cell differentiation, transit amplifying cells, PERK-eIF2α signaling, intestinal organoids, self-renewal
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Animals, Cell Differentiation, Cells, Cultured, Heat-Shock Proteins, Intestinal Mucosa, Mutation, Stem Cells, Signal Transduction, Eukaryotic Initiation Factor-2, eIF-2 Kinase, RNA Interference, RNA, Small Interfering, Mice, Unfolded Protein Response, Endoplasmic Reticulum Stress
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