ERS Respiratory Channel

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Abstract

Background: The loss of functional CF transmembrane conductance regulator (CFTR) has been shown to compromise the regeneration process of the airway epithelium after injury. However, the mechanistic insights remain unclear.

Objective: Exploring the mechanistic role of CFTR in airway epithelial cell differentiation/regeneration.

Methods: Epithelial/mesenchymal markers were assessed by Western Blot (WB) and immunofluorescence in CF and non-CF cells. Wound-closure of differentiated human BCi-NS1.1 cells was analysed by live-cell microscopy and WB. Using CRISPR/Cas9, two novel basal CF cells were generated.

Results: Data show an increased N-cadherin expression only in p.Phe508del-CFTR cells vs p.Gly551Asp- and wt-CFTR cells, albeit both CF cells present a lower TEER vs wt-CFTR cells. Fully differentiated BCi-NS1.1 cells are able to close a wound within 72 h with CFTR protein levels increasing over time. Furthermore, two novel isogenic basal cell lines, BCi-CF1.1 (p.Phe508del/p.Phe508del) and BCi-CF2.1 (p.Gly551Asp/p.Gly551Asp) were successfully generated to study the mechanistic role of CFTR. Results show that BCi-CF1.1 and BCi-CF2.1 cells differentiate into the various airway cell types, including ionocytes. Ongoing studies are characterizing both CF cell models exploring the impact of CFTR variants on airway epithelial differentiation and regeneration.

Conclusion:
Plasma membrane localized p.Gly551Asp-CFTR, albeit not functional, improves epithelial junction organization vs ER-retained p.Phe508del-CFTR. Moreover, wound healing studies suggest that CFTR plays a role in these processes. Novel CF cells with differentiation capacity offer unique models to study CFTR's role in epithelial differentiation and regeneration.

Abstract

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