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Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment

View ORCID ProfileNaveen Kumar, View ORCID ProfileRajendra Kumar Gurumurthy, Pon Ganish Prakash, Shilpa Mary Kurian, Christian Wentland, View ORCID ProfileVolker Brinkmann, View ORCID ProfileHans-Joachim Mollenkopf, View ORCID ProfileTobias Krammer, Christophe Toussaint, View ORCID ProfileAntoine-Emmanuel Saliba, Matthias Biebl, View ORCID ProfileChristian Juergensen, View ORCID ProfileBertram Wiedenmann, View ORCID ProfileThomas F Meyer, View ORCID ProfileCindrilla Chumduri
doi: https://doi.org/10.1101/2021.08.05.455222
Naveen Kumar
1Department of Microbiology, University of Würzburg, Würzburg, Germany
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Rajendra Kumar Gurumurthy
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
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Pon Ganish Prakash
1Department of Microbiology, University of Würzburg, Würzburg, Germany
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Shilpa Mary Kurian
1Department of Microbiology, University of Würzburg, Würzburg, Germany
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Christian Wentland
1Department of Microbiology, University of Würzburg, Würzburg, Germany
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Volker Brinkmann
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
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Hans-Joachim Mollenkopf
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
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Tobias Krammer
5Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
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Christophe Toussaint
5Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
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Antoine-Emmanuel Saliba
5Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
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Matthias Biebl
3Surgical Clinic Campus Charité Mitte, Charité University Medicine, Berlin, Germany
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Christian Juergensen
4Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany
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Bertram Wiedenmann
4Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany
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Thomas F Meyer
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
6Laboratory of Infection Oncology, Institute of Clinical Molecular Biology (IKMB), Christian Albrechts University of Kiel, Kiel, Germany
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Cindrilla Chumduri
1Department of Microbiology, University of Würzburg, Würzburg, Germany
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
4Department of Hepatology and Gastroenterology, Charité University Medicine, Berlin, Germany
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  • For correspondence: cindrilla.chumduri@uni-wuerzburg.de
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Abstract

The gastroesophageal junction (GEJ), where squamous and columnar epithelia meet, is a hotspot for Barrett’s metaplasia development, dysbiosis and carcinogenesis. However, the mechanisms regulating GEJ homeostasis remain unclear. Here, by employing organoids, bulk and single-cell transcriptomics, single-molecule RNA in situ hybridisations and lineage tracing, we identified the spatial organisation of the epithelial, stromal compartment and the regulators that maintain the normal GEJ homeostasis. During development, common KRT8 progenitors generate committed unilineage p63/KRT5-squamous and KRT8-columnar stem cells responsible for the regeneration of postnatal esophagus and gastric epithelium that meet at GEJ. A unique spatial distribution of Wnt regulators in the underlying stromal compartment of these stem cells creates diverging Wnt microenvironments at GEJ and supports their differential regeneration. Further, we show that these tissue-resident stem cells do not possess the plasticity to transdifferentiate to the other lineage with the altered Wnt signals. Our study provides invaluable insights into the fundamental process of GEJ homeostasis and is crucial for understanding disease development.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 06, 2021.
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Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment
Naveen Kumar, Rajendra Kumar Gurumurthy, Pon Ganish Prakash, Shilpa Mary Kurian, Christian Wentland, Volker Brinkmann, Hans-Joachim Mollenkopf, Tobias Krammer, Christophe Toussaint, Antoine-Emmanuel Saliba, Matthias Biebl, Christian Juergensen, Bertram Wiedenmann, Thomas F Meyer, Cindrilla Chumduri
bioRxiv 2021.08.05.455222; doi: https://doi.org/10.1101/2021.08.05.455222
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Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment
Naveen Kumar, Rajendra Kumar Gurumurthy, Pon Ganish Prakash, Shilpa Mary Kurian, Christian Wentland, Volker Brinkmann, Hans-Joachim Mollenkopf, Tobias Krammer, Christophe Toussaint, Antoine-Emmanuel Saliba, Matthias Biebl, Christian Juergensen, Bertram Wiedenmann, Thomas F Meyer, Cindrilla Chumduri
bioRxiv 2021.08.05.455222; doi: https://doi.org/10.1101/2021.08.05.455222

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