Abstract
Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids” and “organoids” can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTransmembrane Conductance Regulator (CFTR) gene, mapped on the long arm of chromosome7
The personalized medicine approach in CF needs that patient-derived samples from the airways are cultured in a way that is more attainable to reproduce the respiratory microenvironment
Airway cell-based spheroids and organoids are being implemented in the past decades to establish a study model that would guarantee a solid alternative to the gold standard in CF drug studies, i.e., electrophysiological studies in differentiated cultures at air–liquid interface (ALI) conditions
Summary
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF. Class I mutations may lead to premature stop codons, causing a lack of protein synthesis (i.e., G542X, W1282X). Class II mutations cause defective protein processing, which causes improper folding of CFTR during protein synthesis and leading to ER-mediated degradation through the proteasome (i.e., F508del, N1303K). Class III mutations cause defective channel regulation (i.e., G551D, S549N); Class IV mutations determine defective channel conduction (i.e., R117H, R334W); Class V mutations are responsible for reduced protein synthesis (i.e., A455E, 3849 + 10kbC → T); Class VI mutations cause reduced protein stability, which includes rescued-F508del-CFTR or Q1411X [2,3]. The diminished chloride and bicarbonate secretion into the airway lumen, exerted by the CFTR protein, is responsible for sticky mucus accumulating [11]. The specific role of the different cell types in ion and fluid homeostasis and pathology of the CF airway disease has not been exactly defined yet
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