Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease

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ABSTRACT

The intestinal epithelium is a highly organized tissue. The establishment of epithelial cell polarity, with distinct apical and basolateral plasma membrane domains, is pivotal for both barrier formation and for the uptake and vectorial transport of nutrients. The establishment of cell polarity requires a specialized subcellular machinery to transport and recycle proteins to their appropriate location. In order to understand and treat polarity-associated diseases, it is necessary to understand epithelial cell-specific trafficking mechanisms. In this Review, we focus on cell polarity in the adult mammalian intestine. We discuss how intestinal epithelial polarity is established and maintained, and how disturbances in the trafficking machinery can lead to a polarity-associated disorder, microvillus inclusion disease (MVID). Furthermore, we discuss the recent developments in studying MVID, including the creation of genetically manipulated cell lines, mouse models and intestinal organoids, and their uses in basic and applied research.

Abstract

Summary: Microvillus inclusion disease serves as a useful model to enhance our understanding of the intestinal trafficking and polarity machinery in health and disease.

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Most cited references 132

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Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.

Gerald Schwank, Bon-Kyoung Koo, Valentina Sasselli … (2013)

Single murine and human intestinal stem cells can be expanded in culture over long time periods as genetically and phenotypically stable epithelial organoids. Increased cAMP levels induce rapid swelling of such organoids by opening the cystic fibrosis transmembrane conductor receptor (CFTR). This response is lost in organoids derived from cystic fibrosis (CF) patients. Here we use the CRISPR/Cas9 genome editing system to correct the CFTR locus by homologous recombination in cultured intestinal stem cells of CF patients. The corrected allele is expressed and fully functional as measured in clonally expanded organoids. This study provides proof of concept for gene correction by homologous recombination in primary adult stem cells derived from patients with a single-gene hereditary defect. Copyright © 2013 Elsevier Inc. All rights reserved.

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A functional CFTR assay using primary cystic fibrosis intestinal organoids.

Johanna F. Dekkers, Caroline L Wiegerinck, Hugo de Jonge … (2013)

We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.

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ERM proteins and merlin: integrators at the cell cortex.

Anthony Bretscher, Kevin Edwards, Richard Fehon (2002)

A fundamental property of many plasma-membrane proteins is their association with the underlying cytoskeleton to determine cell shape, and to participate in adhesion, motility and other plasma-membrane processes, including endocytosis and exocytosis. The ezrin-radixin-moesin (ERM) proteins are crucial components that provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways. The closely related tumour suppressor merlin shares many properties with ERM proteins, yet also provides a distinct and essential function.

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Author and article information

Journal

Journal ID (nlm-ta): Dis Model Mech

Journal ID (iso-abbrev): Dis Model Mech

Journal ID (publisher-id): DMM

Journal ID (hwp): dmm

Title: Disease Models & Mechanisms

Publisher: The Company of Biologists Ltd

ISSN (Print): 1754-8403

ISSN (Electronic): 1754-8411

Publication date (Print): 1 February 2018

Publication date PMC-release: 1 February 2018

Volume: 11

Issue: 2

Electronic Location Identifier: dmm031088

Affiliations

[1 ]Division of Paediatrics, Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital , 3584 CT, Utrecht, The Netherlands

[2 ]Regenerative Medicine Center Utrecht, University Medical Centre (UMC) Utrecht , 3584 CT, Utrecht, The Netherlands

Author notes

[*]

Present address: Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands.

[‡]

These authors contributed equally to this work

[§ ]Author for correspondence ( s.middendorp@ 123456umcutrecht.nl )

Author information

Sabine Middendorp http://orcid.org/0000-0002-0925-0095

Article

Publisher ID: DMM031088

DOI: 10.1242/dmm.031088

PMC ID: 5894939

PubMed ID: 29590640

SO-VID: f144e3dd-6625-4440-9f5e-85c689319163

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

History

Funding

Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, http://dx.doi.org/10.13039/501100003246;

Award ID: VIDI 016.146.353

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