Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

Abstract

Summary: The pathogenesis of idiopathic pulmonary fibrosis (IPF), an intractable interstitial lung disease, is unclear. Recessive mutations in some genes implicated in Hermansky-Pudlak syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity that is similar to IPF. We previously reported that HPS1−/− embryonic stem cell-derived 3D lung organoids showed fibrotic changes. Here, we show that the introduction of all HPS mutations associated with HPSIP promotes fibrotic changes in lung organoids, while the deletion of HPS8, which is not associated with HPSIP, does not. Genome-wide expression analysis revealed the upregulation of interleukin-11 (IL-11) in epithelial cells from HPS mutant fibrotic organoids. IL-11 was detected predominantly in type 2 alveolar epithelial cells in end-stage IPF, but was expressed more broadly in HPSIP. Finally, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in HPS4−/− organoids, suggesting IL-11 as a therapeutic target. hPSC-derived 3D lung organoids are, therefore, a valuable resource to model fibrotic lung disease. : Pulmonary fibrosis is an intractable disease that can be familial or idiopathic. Strikoudis et al. modeled pulmonary fibrosis in lung organoids generated from embryonic stem cells with mutations in Hermansky-Pudlak syndrome genes that strongly predispose to this disease and demonstrate an essential role for interleukin-11 in the fibrotic process. Keywords: organoids, lung, human pluripotent stem cells, Hermansky-Pudlak syndrome, pulmonary fibrosis, interleukin-11, disease modeling