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bioRxiv · 10.1101/2022.06.15.496102

Modeling of Aberrant Epithelial Reprogramming in Idiopathic Pulmonary Fibrosis using Human Induced Pluripotent Stem Cell-derived Alveolar Organoids

Ptasinski, V.·Monkley, S. J.·Ost, K.·Tammia, M.·Overed-Sayer, C.·Hazon, P.·Wagner, D. E.·Murray, L. A.
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Abstract

Repeated injury of the lung epithelium is proposed to be a main driver of idiopathic pulmonary fibrosis (IPF). However, none of the available therapies target the epithelium and there is a limited amount of human models of fibrotic epithelial damage with suitability for drug screening and discovery. We developed a model of the epithelial reprogramming seen in IPF using alveolar organoids derived from human induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. This fibrosis cocktail induced persistent epithelial reprogramming and expression of extracellular matrix. Deconvolution of RNA-seq data indicated that the fibrosis cocktail increased the proportion of cells with the KRT5-/KRT17+ aberrant basaloid phenotype, recently identified in the lungs of IPF patients. Treatment with nintedanib and pirfenidone had effects on markers of extracellular matrix, pro-fibrotic mediators and epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.

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Ptasinski, V., Monkley, S. J., Ost, K., Tammia, M., Overed-Sayer, C., Hazon, P., Wagner, D. E., Murray, L. A.. 2022-06-15. Modeling of Aberrant Epithelial Reprogramming in Idiopathic Pulmonary Fibrosis using Human Induced Pluripotent Stem Cell-derived Alveolar Organoids. https://doi.org/10.1101/2022.06.15.496102

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