Title: Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease.
Authors: Alysandratos, Konstantinos-Dionysios; Russo, Scott J; Petcherski, Anton; Taddeo, Evan P; Acín-Pérez, Rebeca; Villacorta-Martin, Carlos; Jean, J C; Mulugeta, Surafel; Rodriguez, Luis R; Blum, Benjamin C; Hekman, Ryan M; Hix, Olivia T; Minakin, Kasey; Vedaie, Marall; Kook, Seunghyi; Tilston-Lunel, Andrew M; Varelas, Xaralabos; Wambach, Jennifer A; Cole, F Sessions; Hamvas, Aaron; Young, Lisa R; Liesa, Marc; Emili, Andrew; Guttentag, Susan H; Shirihai, Orian S; Beers, Michael F; Kotton, Darrell N
Published In Cell Rep, (2021 Aug 31)
Abstract: Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.
PubMed ID: 34469722
MeSH Terms: Alveolar Epithelial Cells/metabolism*; Alveolar Epithelial Cells/pathology; Animals; Cell Line; Cell Proliferation; Energy Metabolism; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells/metabolism*; Induced Pluripotent Stem Cells/pathology; Inflammation Mediators/metabolism; Lung Diseases, Interstitial/genetics*; Lung Diseases, Interstitial/metabolism; Lung Diseases, Interstitial/pathology; Mice, Knockout; Mutation; NF-kappa B/metabolism; Phenotype; Proteostasis; Pulmonary Surfactant-Associated Protein C/genetics*; Pulmonary Surfactant-Associated Protein C/metabolism; Signal Transduction