RT Journal Article
SR Electronic
T1 Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in an iPSC-derived air-liquid interface model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 830109
DO 10.1101/830109
A1 Eva Schruf
A1 Victoria Schroeder
A1 Huy Q. Le
A1 Tanja Schönberger
A1 Dagmar Raedel
A1 Emily L. Stewart
A1 Katrin Fundel-Clemens
A1 Teresa Bluhmki
A1 Sabine Weigle
A1 Michael Schuler
A1 Matthew J. Thomas
A1 Ralf Heilker
A1 Megan J. Webster
A1 Martin Dass
A1 Manfred Frick
A1 Birgit Stierstorfer
A1 Karsten Quast
A1 James P. Garnett
YR 2019
UL http://biorxiv.org/content/early/2019/11/04/830109.abstract
AB An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is a process often observed in patients suffering from idiopathic pulmonary fibrosis (IPF), a fatal disease characterized by progressive fibrotic lung remodeling. However, the origin of this dysfunctional epithelium remains unknown.In this study, we aimed to investigate the effects of a pro-fibrotic milieu, similar to that found in an IPF lung, on human alveolar epithelial progenitor cell differentiation. We developed an induced pluripotent stem cell (iPSC)-derived air-liquid interface (ALI) model of alveolar type II (ATII)-like cell differentiation and stimulated it with an IPF-relevant cocktail (IPF-RC), composed of cytokines previously reported to be elevated in IPF lungs. iPSC-derived cultures express ATII markers and contain lamellar body-like structures. Stimulation with IPF-RC during the last two weeks of differentiation increases secretion of IPF biomarkers. Transcriptome analysis of IPF-RC treated cultures reveals significant overlap with human IPF data and enrichment of transcripts associated with extracellular matrix organization. IPF-RC stimulation further impairs ATII differentiation by driving a shift towards an airway epithelial-like expression signature.In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization in vitro. Our findings reveal how aberrant alveolar epithelial progenitor cell differentiation in a pro-fibrotic environment could contribute to alveolar bronchiolization in the distal IPF lung.SOURCE OF SUPPORT The research was funded by Boehringer Ingelheim Pharma GmbH & Co. KG.