Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC-derived air-liquid interface model.

Clicks: 182
ID: 104292
2020
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause that is characterized by progressive fibrotic lung remodeling. An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is often observed in IPF. However, the origin of this dysfunctional distal lung epithelium remains unknown due to a lack of suitable human model systems. In this study, we established a human induced pluripotent stem cell (iPSC)-derived air-liquid interface (ALI) model of alveolar epithelial type II (ATII)-like cell differentiation that allows us to investigate alveolar epithelial progenitor cell differentiation in vitro. We treated this system with an IPF-relevant cocktail (IPF-RC) to mimic the pro-fibrotic cytokine milieu present in IPF lungs. Stimulation with IPF-RC during differentiation increases secretion of IPF biomarkers and RNA sequencing (RNA-seq) of these cultures reveals significant overlap with human IPF patient data. IPF-RC treatment further impairs ATII differentiation by driving a shift toward an airway epithelial-like expression signature, providing evidence that a pro-fibrotic cytokine environment can influence the proximo-distal differentiation pattern of human lung epithelial cells. In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization of the lung epithelium in vitro.
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Authors Schruf, Eva;Schroeder, Victoria;Le, Huy Q;Schönberger, Tanja;Raedel, Dagmar;Stewart, Emily L;Fundel-Clemens, Katrin;Bluhmki, Teresa;Weigle, Sabine;Schuler, Michael;Thomas, Matthew J;Heilker, Ralf;Webster, Megan J;Dass, Martin;Frick, Manfred;Stierstorfer, Birgit;Quast, Karsten;Garnett, James P;
Journal faseb journal : official publication of the federation of american societies for experimental biology
Year 2020
DOI 10.1096/fj.201902926R
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