Abstract
Idiopathic Pulmonary Fibrosis (IPF) is characterized by scarring and remodeling of lung tissue, leading to progressive pulmonary dysfunction. Currently, very little is known about the steps involved in disease initiation and progression because models of IPF poorly replicate these processes. However, understanding the pathogenesis of IPF is essential to developing effective therapies. To address this, we developed a scaffold-based human co-culture alveolar organoid model that utilizes healthy and IPF human primary lung fibroblasts and induced pluripotent stem cell-derived alveolar type 2 (iAT2) cells carrying the surfactant protein C (SFTPC) 173T mutation of familial IPF, or their syngeneic corrected controls, to recapitulate epithelial-mesenchymal cellular communication during fibrosis initiation and progression. We found that the interaction between epithelial cells and fibroblasts plays a key role in inducing fibrotic responses in this model, with the secretion of chemokines, cytokines, TGFβ, and matrix metalloproteinases that mirror those observed in the serum of patients with pulmonary fibrosis. Single-cell RNA sequencing revealed the emergence of many cell subtypes observed in progressive lung fibrosis, along with key cellular interactions that correlated with the initial upregulation of fibrosis pathways, extracellular matrix (ECM) remodeling, inflammation, and changes in lipid metabolism. The anti-fibrotic compounds, Nintedanib and the TGFβ inhibitor, SB431542, demonstrated dose-dependent efficacy in the model, with IC50 values comparable to those observed in the clinic, and significantly reduced secretion of fibrosis-related factors. Overall, this study shows that the three-dimensional cell co-culture organoid effectively models progressive lung fibrosis, facilitating the investigation of epithelial-mesenchymal interactions and serving as a patient-relevant model to better predict the efficacy of therapeutics in the clinic.