Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, interstitial lung disease with a median survival of 2-3 years. Its etiology is unclear but environmental and genetic risk factors indicate that alveolar epithelial type 2 cells (AT2s) play a pivotal role. Mutations in surfactant protein (SP) genes compromise AT2s function and viability, reducing its capacity to regenerate damaged alveolar epithelial tissue. This function is further compromised by infection-induced lung injury. Environmental stimuli together with genetic predisposition in IPF patients result in an aberrant fibrotic response driven by AT2s. The study of this interaction has been hampered by the lack of adequate human IPF models. To better understand this genotype-phenotype relationship, we created an organoid platform using IPF patient-derived human induced pluripotent stem cells (hiPSCs) carrying a SP mutation and the CRISPR corrected isogenic control. Via directed differentiation, we generated lung progenitors and matured them in 3D conditions to obtain a population of AT2s expressing SP, which were enriched and exposed to H1N1 influenza A virus. RNA sequencing data showed that, upon infection, transcriptome profiling revealed overrepresented stress-related processes including ?inflammatory and immune response?, ?oxidation-reduction process and ?defense response to virus? in mutant IPF cells compared with the wild-type cells. The analysis also revealed differentially expressed genes involved in AT2s function. Our data validates AT2s as a robust in vitro model to better understand the connection between infectious agents and IPF disease progression.