Abstract
Introduction: Dysregulation of the alveolar epithelium by repeated injury is recognised as a driver of idiopathic pulmonary fibrosis (IPF). However, access to relevant pre-clinical models of alveolar epithelial injury in IPF is limited.
Aims and objectives: We sought to develop a disease model of alveolar epithelial injury in IPF using alveolar epithelial organoids derived from human induced pluripotent stem cells (iPSCs) for drug discovery.
Methods: Alveolar epithelial organoids were derived from iPSCs and treated with a fibrosis cocktail (FC) of the pro-fibrotic and inflammatory cytokines TGFß, TNFa, PDGF-AB and LPA. IPF-related changes were evaluated by RNA-Seq, qRT-PCR, and Western blot. To evaluate the potential of this system for testing anti-fibrotic compounds, we performed prophylactic treatment with the marketed IPF drug nintedanib for 72 h and screened for well-known hallmarks of IPF by qRT-PCR.
Results: The FC induced changes known to be observed in IPF, such as epithelial injury and reprogramming (e.g. loss of SFTPC expression and induced VIM expression), production of extracellular matrix and induction of cellular senescence- associated genes. Interestingly, FC treatment also increased expression of KRT17 and KRT8, both recently identified in single-cell RNA-Seq studies as markers of dysregulated epithelial repair in IPF. Treatment with nintedanib partially prevented transcriptional changes in extracellular matrix components, matrix-modifying enzymes and mediators of several signaling pathways associated with IPF.
Conclusions: FC treatment of iPSC-derived alveolar epithelial cells successfully models several key aspects of IPF and some of these changes can be prevented with nintedanib, demonstrating that this system can be used for disease modeling of IPF and drug discovery.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA2051.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021