en
Doctoral thesis
English

Mechanisms Underlying the Polarization of Cystic Fibrosis Airway Epithelial Cells

ContributorsIdris, Tahir
Number of pages213
Imprimatur date2023
Defense date2023
Abstract

Cystic Fibrosis (CF) is an autosomal, recessive, multi-organ disorder and is the most common lethal genetic disorder in the Caucasian population, affecting approximately 1 in 2500 Caucasians, with 1 in 25 people being carriers. CF is caused by mutations to the CF transmembrane conductance regulator (CFTR), an anion channel expressed in epithelial cells of many organs. Pulmonary manifestations are the main cause of CF mortality and morbidity and is characterized by chronic infections, exacerbated inflammation, mucus plugging of the trachea-bronchial airway tract, eventually leading to bronchiectasis and lung failure. There are currently no cures for CF.

CF airway disease can be attributed to a loss of cell polarity and barrier integrity thereby predisposing the epithelium to increased bacterial infections. Airway epithelial apicobasal polarity is dependent on a well-organized cytoskeletal and junctional network and proper establishment of extracellular matrix (ECM) proteins. In CF, there is increasing evidence of defects in the polarity and the cytoskeletal organization, however, more work is necessary to fully uncover these defects. Understanding the mechanisms underlying the polarization of the CF airway epithelium is highly crucial for the development of therapies against bacterial infections in CF.

The first part of my thesis work focused on unravelling the role of Vav3, an important guanine exchange nucleotide factor (GEF) and a Rho GTPase activator, in the establishment of apical bacterial docking stations involving the ECM protein fibronectin and its receptor β1-integrin in CF. In this study, we showed that Vav3, fibronectin and β1-integrin are overexpressed and ectopically localized at the apical surface of CF airway epithelia leading to increased Pseudomonas aeruginosa (Pa) adhesion, the leading cause of airway infections in CF, and hinting towards a defect in CF polarity.

Next, I further explored the concept of a polarity defect and attempted to decipher it by investigating signaling pathways that regulate the polarization process. In CF, the concept of an interplay between the TGF-β, Wnt and Akt pathways in the regulation of polarization has not been studied. Here, I report an hyperactivation of the TGF-β pathway and an inhibition of the Wnt pathway, and this is mediated by an aberrant Akt signaling in CF human airway epithelial cells (HAECs). These abnormalities lead to the establishment of fibronectin at the apical surface of CF airway epithelial cells. Pharmacological modulation of these pathways was able to prevent the ectopic localization of fibronectin and restoration of cell polarity.

Finally, I developed human airway organoids from NCF and CF HAECs to further investigate and characterize the polarity defect in CF. Indeed, I was able to generate these organoids and structural abnormalities were observed in CF airway organoids. Altogether our studies demonstrate the importance of the polarization process in airway epithelial biology and abnormalities in key signaling molecules can result in epithelial polarity defect and a predisposition of the CF airway epithelium to bacterial infections. Therefore, research into these signaling events and molecules could serve as an important therapeutic strategy to prevent bacterial infections in CF airway epithelium.

eng
Keywords
  • Polarity
  • Airway epithelium
  • Cystic fibrosis
  • Bacterial infections
  • Signaling pathways
Citation (ISO format)
IDRIS, Tahir. Mechanisms Underlying the Polarization of Cystic Fibrosis Airway Epithelial Cells. 2023. doi: 10.13097/archive-ouverte/unige:170680
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Creation08/04/2023 9:07:52 AM
First validation08/15/2023 5:34:11 AM
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