ER stress induces epithelial differentiation in the mouse oesophagus.
OBJECTIVE
Stress in the endoplasmic reticulum (ER) leads to activation of the unfolded protein response (UPR). Xbp1, a key component of the UPR has recently been linked to the risk of developing oesophageal squamous cell carcinoma, suggesting an important role for the UPR in the oesophageal epithelium. Here we examined the role of ER stress and the UPR in oesophageal epithelial homoeostasis.


METHODS
We examined the expression of components of the UPR in the oesophageal epithelium. We used a pharmacological approach and a genetic approach to examine the effects of ER stress in vivo in the mouse oesophagus. The oesophagus of these mice was examined using immunohistochemistry and real-time reverse transcription (RT)-PCR.


RESULTS
Components of the UPR were heterogeneously expressed in the basal layer of the epithelium. Induction of ER stress by 24-h treatment with thapsigargin resulted in depletion of proliferating cells in the basal layer of the oesophagus and induced differentiation. We next activated the UPR by inducible deletion of the major ER chaperone Grp78 in Ah1Cre-Rosa26-LacZ-Grp78(-/-) mice in which mutant cells could be traced by expression of LacZ. In these mice LacZ-positive mutant cells in the basal layer lost their proliferative capacity, migrated towards the oesophageal lumen and were replaced by LacZ-negative non-mutant cells. We observed no apoptosis in mutant cells.


CONCLUSIONS
These results show that ER stress induces epithelial differentiation in precursor cells in the oesophageal epithelium. This UPR induced differentiation may serve as a quality control mechanism that protects against oesophageal cancer development.
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Sanne L
SL
Rosekrans
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Jarom
J
Heijmans
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Nikè V J A
NV
Büller
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Jessica
J
Westerlund
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Amy S
AS
Lee
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Vanesa
V
Muncan
Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Gijs R
GR
van den Brink
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D004947:Esophagus / Q000166:cytology*; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007783:Lactones / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D012717:Sesquiterpenes / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology; D056811:Unfolded Protein Response / Q000502:physiology
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007783:Lactones; D012717:Sesquiterpenes; C046319:thapsigargicin