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

Schruf, E.; Schroeder, V.; Le, H. Q.; Schoenberger, T.; Raedel, D.; Stewart, E. L.; Fundel-Clemens, K.; Bluhmki, T.; Weigle, S.; Schuler, M.; Thomas, M. J.; Heilker, R.; Webster, M. J.; Dass, M.; Frick, M.; Stierstorfer, B.; Quast, K.; Garnett, J. P.

doi:10.1101/830109

bioRxiv · 10.1101/830109

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

Schruf, E.·Schroeder, V.·Le, H. Q.·Schoenberger, T.·Raedel, D.·Stewart, E. L.·Fundel-Clemens, K.·Bluhmki, T.·Weigle, S.·Schuler, M.·Thomas, M. J.·Heilker, R.·Webster, M. J.·Dass, M.·Frick, M.·Stierstorfer, B.·Quast, K.·Garnett, J. P.

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Abstract

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.\n\nIn 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.\n\nIn 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.\n\nSOURCE OF SUPPORTThe research was funded by Boehringer Ingelheim Pharma GmbH & Co. KG.

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Schruf, E., Schroeder, V., Le, H. Q., Schoenberger, T., Raedel, D., Stewart, E. L., Fundel-Clemens, K., Bluhmki, T., Weigle, S., Schuler, M., Thomas, M. J., Heilker, R., Webster, M. J., Dass, M., Frick, M., Stierstorfer, B., Quast, K., Garnett, J. P.. 2019-11-04. Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in an iPSC-derived air-liquid interface model. https://doi.org/10.1101/830109

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