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Special Issue "Epithelial Ion Transport in Health and Disease"

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Guest Editor

Biosciences Institute, University Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Interests: epithelial ion transport; ion channels and transporters; cell signaling; pH regulation; cystic fibrosis; pancreatitis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Robert Tarran

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The Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Interests: Ca²⁺ signaling; epithelial transport; regulation of ion channels by extracellular proteins; cystic fibrosis

Special Issue Information

Dear Colleagues,

The transport of ions by epithelial cells is essential for a wide range of physiologically important processes, such as acid–base and fluid balance, defense against pathogens, the digestion and absorption of nutrients, efficient sensory transduction, and tissue differentiation as well as repair. Dysfunction in epithelial ion transport underlies many diseases, such as secretory diarrheas, hypertension, COPD, cystic fibrosis, ARDS, pancreatitis, and hydrocephalus, to name just a few. This Special Issue will bring together original research and review articles related to the functional and pathological roles of ion transport in epithelial tissues in health and disease. It will highlight new discoveries, approaches, and technical developments in epithelial research. The main feature of this Special Issue is to highlight emerging new roles played by ion transporters and channels in epithelia, as well as how this information is being harnessed to develop new therapeutic strategies for important human diseases.

Dr. Michael Gray
Prof. Dr. Robert Tarran
Guest Editors

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Keywords

epithelial ion transport
epithelial fluid transport
epithelial signaling
epithelial defense
epithelial repair
epithelial differentiation
lungs
gastrointestinal tract
reproductive tract
kidney
liver
pancreas
choroid plexus
salivary glands
diseases of ion transport
chronic inflammatory diseases

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Research

Open AccessArticle

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes

Juliet W. Lefferts

Marlou C. Bierlaagh

Suzanne Kroes

Natascha D. A. Nieuwenhuijze

Heleen N. Sonneveld van Kooten

Sam F. B. van Beuningen

Cornelis K. van der Ent

and

Jeffrey M. Beekman

Int. J. Mol. Sci. 2023, 24(19), 14539; https://doi.org/10.3390/ijms241914539 - 26 Sep 2023

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Abstract

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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Open AccessArticle

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

Azam Salari

Renjie Xiu

Mahdi Amiri

Sophia Theres Pallenberg

and

Int. J. Mol. Sci. 2023, 24(18), 14214; https://doi.org/10.3390/ijms241814214 - 18 Sep 2023

Viewed by 220

Abstract

Studies in human colonic cell lines and murine intestine suggest the presence of a Ca²⁺-activated anion channel, presumably TMEM16a. Is there a potential for fluid secretion in patients with severe cystic fibrosis transmembrane conductance regulator (CFTR) mutations by activating this alternative pathway? Two-dimensional nondifferentiated colonoid–myofibroblast cocultures resembling transit amplifying/progenitor (TA/PE) cells, as well as differentiated monolayer (DM) cultures resembling near-surface cells, were established from both healthy controls (HLs) and patients with severe functional defects in the CFTR gene (PwCF). F508del mutant and CFTR knockout (null) mice ileal and colonic mucosa was also studied. HL TA/PE monolayers displayed a robust short-circuit current response (ΔI_eq) to UTP (100 µM), forskolin (Fsk, 10 µM) and carbachol (CCH, 100 µM), while ΔI_eq was much smaller in differentiated monolayers. The selective TMEM16a inhibitor Ani9 (up to 30 µM) did not alter the response to luminal UTP, significantly decreased Fsk-induced ΔI_eq, and significantly increased CCH-induced ΔI_eq in HL TA/PE colonoid monolayers. The PwCF TA/PE and the PwCF differentiated monolayers displayed negligible agonist-induced ΔI_eq, without a significant effect of Ani9. When TMEM16a was localized in intracellular structures, a staining in the apical membrane was not detected. TMEM16a is highly expressed in human colonoid monolayers resembling transit amplifying cells of the colonic cryptal neck zone, from both HL and PwCF. While it may play a role in modulating agonist-induced CFTR-mediated anion currents, it is not localized in the apical membrane, and it has no function as an apical anion channel in cystic fibrosis (CF) and healthy human colonic epithelium. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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Special Issue "Epithelial Ion Transport in Health and Disease"

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