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Cells
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Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the...
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Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the Present and the Future

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 17580

Special Issue Editor

Prof. Dr. Graziella Messina

E-Mail Website
Guest Editor
Department of Biosciences, University of Milan, via Celoria 26, 20154 Milan, Italy
Interests: stem cells and regenerative medicine; cystic fibrosis; skeletal muscle development and regeneration; role of stem cells and tissue niche in the pathophysiology of cystic fibrosis and muscular dystrophies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The autosomal recessive disease cystic fibrosis (CF) was once untreatable and deadly in childhood, but now most patients survive to adulthood. CF research has greatly intensified following the discovery of the CF transmembrane conductance regulator (CFTR) gene, which has more than 2000 different mutations. Since the CFTR gene was cloned in 1989, there has been great motivation to develop strategies, such as gene therapy and drug discovery, for restoring the defective protein. In addition to the symptomatic therapeutic approaches that target cellular events downstream the CFTR failure, other strategies focused on the basic CFTR defect have emerged. For patients with common mutations such as F508del, CFTR modulators are life-transforming and may even prevent major complications if started early in childhood. For some patients with rare CFTR mutations, a treatment path still needs to be developed. This Special Issue offers an Open Access forum that aims to bring together original research and review articles addressing cellular and molecular mechanisms at the basis of the pathophysiology of CF and to suggest potential and promising therapeutic approaches to cure CF. We hope to provide a stimulating resource for this fascinating subject.

Prof. Graziella Messina
Guest Editor

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Keywords

  • Cystic fibrosis
  • CFTR
  • F508del
  • Infection
  • Inflammation
  • Gene therapy
  • Cell therapy
  • CFTR corrector/potentiator

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Published Papers (4 papers)

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Research

15 pages, 3576 KiB  
Article
Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting
by Matteo Puccetti, Marilena Pariano, Giorgia Renga, Ilaria Santarelli, Fiorella D’Onofrio, Marina M. Bellet, Claudia Stincardini, Andrea Bartoli, Claudio Costantini, Luigina Romani, Maurizio Ricci and Stefano Giovagnoli
Cells 2021, 10(7), 1601; https://doi.org/10.3390/cells10071601 - 25 Jun 2021
Cited by 18 | Viewed by 2649
Abstract
Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), [...] Read more.
Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), a ligand of the aryl hydrocarbon receptor (AhR), may encompass such an activity. We resorted to biopharmaceutical technologies in order to deliver 3-IAld directly into the lung, via dry powder inhalation, or into the gut, via enteric microparticles, in murine models of CF infection and inflammation. We found the site-specific delivery of 3-IAld to be an efficient strategy to restore immune and microbial homeostasis in CF organs, and mitigate lung and gut inflammatory pathology in response to fungal infections, in the relative absence of local and systemic inflammatory toxicity. Thus, enhanced delivery to target organs of AhR agonists, such as 3-IAld, may pave the way for the development of safe and effective anti-inflammatory agents in CF. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the Present and the Future)
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15 pages, 408 KiB  
Article
Ionocytes and CFTR Chloride Channel Expression in Normal and Cystic Fibrosis Nasal and Bronchial Epithelial Cells
by Paolo Scudieri, Ilaria Musante, Arianna Venturini, Daniela Guidone, Michele Genovese, Federico Cresta, Emanuela Caci, Alessandro Palleschi, Marco Poeta, Francesca Santamaria, Fabiana Ciciriello, Vincenzina Lucidi and Luis J. V. Galietta
Cells 2020, 9(9), 2090; https://doi.org/10.3390/cells9092090 - 13 Sep 2020
Cited by 45 | Viewed by 6346
Abstract
The airway epithelium contains ionocytes, a rare cell type with high expression of Forkhead Box I1 (FOXI1) transcription factor and Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel that is defective in cystic fibrosis (CF). Our aim was [...] Read more.
The airway epithelium contains ionocytes, a rare cell type with high expression of Forkhead Box I1 (FOXI1) transcription factor and Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel that is defective in cystic fibrosis (CF). Our aim was to verify if ionocyte development is altered in CF and to investigate the relationship between ionocytes and CFTR-dependent chloride secretion. We collected nasal cells by brushing to determine ionocyte abundance. Nasal and bronchial cells were also expanded in vitro and reprogrammed to differentiated epithelia for morphological and functional studies. We found a relatively high (~3%) ionocyte abundance in ex vivo nasal samples, with no difference between CF and control individuals. In bronchi, ionocytes instead appeared very rarely as previously reported, thus suggesting a possible proximal–distal gradient in human airways. The difference between nasal and bronchial epithelial cells was maintained in culture, which suggests an epigenetic control of ionocyte development. In the differentiation phase of the culture procedure, we used two media that resulted in a different pattern of CFTR expression: confined to ionocytes or more broadly expressed. CFTR function was similar in both conditions, thus indicating that chloride secretion equally occurs irrespective of CFTR expression pattern. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the Present and the Future)
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18 pages, 2940 KiB  
Article
KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
by Luis Sousa, Ines Pankonien, Luka A Clarke, Iris Silva, Karl Kunzelmann and Margarida D Amaral
Cells 2020, 9(7), 1607; https://doi.org/10.3390/cells9071607 - 2 Jul 2020
Cited by 12 | Viewed by 3841
Abstract
Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, [...] Read more.
Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the Present and the Future)
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20 pages, 3041 KiB  
Article
Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model
by Claudia Mazio, Laura S. Scognamiglio, Rossella De Cegli, Luis J. V. Galietta, Diego Di Bernardo, Costantino Casale, Francesco Urciuolo, Giorgia Imparato and Paolo A. Netti
Cells 2020, 9(6), 1371; https://doi.org/10.3390/cells9061371 - 1 Jun 2020
Cited by 9 | Viewed by 3429
Abstract
Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of [...] Read more.
Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cystic Fibrosis: The Past, the Present and the Future)
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