Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies

Abstract

Recent advances in the management of cystic fibrosis (CF) target underlying defects in the CF transmembrane conductance regulator (CFTR) protein, but efficacy analyses remain limited to specific genotype-based subgroups. Patient-derived model systems may therefore aid in expanding access to these drugs. Brushed human nasal epithelial cells (HNEs) are an attractive tissue source, but it remains unclear how faithfully they recapitulate human bronchial epithelial cell (HBE) CFTR activity. We examined this gap using paired, brushed HNE/HBE samples from pediatric CF subjects with a wide variety of CFTR mutations cultured at the air-liquid interface. Growth and structural characteristics for the two cell types were similar, including differentiation into mature respiratory epithelia. In electrophysiologic analysis, no correlation was identified between nasal and bronchial cultures in baseline resistance or epithelial sodium channel (ENaC) activity. Conversely, robust correlation was demonstrated between nasal and bronchial cultures in both stimulated and inhibited CFTR activity. There was close correlation in modulator-induced change in CFTR activity, and CFTR activity in both cell types correlated with in vivo sweat chloride measurements. These data confirm that brushed HNE cell cultures recapitulate the functional CFTR characteristics of HBEs with fidelity and are therefore an appropriate noninvasive HBE surrogate for individualized CFTR analysis.

ORKAMBI-Mediated Rescue of Mucociliary Clearance in Cystic Fibrosis Primary Respiratory Cultures Is Enhanced by Arginine Uptake, Arginase Inhibition, and Promotion of Nitric Oxide Signaling to the Cystic Fibrosis Transmembrane Conductance Regulator Channel

“…But, overall, the magnitude of the responses to the interventions targeting the NO signaling pathway and the CFTR modulators, VX-809 and VX-770, is similar. These findings are consistent with those reported by Brewington et al, 2018, showing that nasal epithelial cultures serve as adequate surrogates for bronchial cultures with respect to modulator effects on F508del-CFTR channel function. Our studies of CBF plus MCCV support the claim that the effect of modulators on CF-associated phenotypes can also be modeled in nasal epithelial cultures.…”

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Primary, reprogrammed and engineered human cell models have become important tools to identify novel pharmacotherapies. The effects of certain therapies may also be exploited at an individual level in ex vivo patient-derived specimens, such as primary bronchial/nasal epithelial cells, and intestinal/respiratory organoids (Fulcher and Randell, 2013;Dekkers et al, 2016a;Dekkers et al, 2016b;Pranke et al, 2017;Awatade et al, 2018;Brewington et al, 2018;Chen et al, 2018;Berkers et al, 2019;Merket et al, 2019). As these cell models recapitulate several features of the parental organ, they are useful to understand the impact of genetic factors on individual disease and predict clinical efficacy of therapies.…”

A marine-sourced fucoidan solution inhibits Toll-like-receptor-3-induced cytokine release by human bronchial epithelial cells

“…Their respective ciliary activities react to various agonists and antagonists in a similar manner [43]. In experiments on nasal and bronchial epithelial cells harvested from children with cystic fibrosis (with a wide variety of CFTR mutations), the cell types' stimulated and inhibited levels of CFTR were similar [44]. In other studies of human bronchial and nasal epithelial cells, levels of cytokine and chemokine release in vitro were similar for both non-stimulated cells and cells stimulated with TNF-α, IL-1β, IL-13 or even rhinovirus infection [45][46][47].…”