B77-05 Human IPSC-Derived Lung Organoids as an in Vitro Model to Evaluate Drug Responsiveness in Idiopathic Pulmonary Fibrosis (IPF)

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive extracellular matrix deposition, resulting in impaired respiratory function. Current pharmacological options are limited, and human models are scarce, underscoring the need for physiologically relevant platforms for drug evaluation. Here, we generated alveolar epithelial cell-enriched lung organoids from human induced pluripotent stem cells (iPSCs) using extracellular matrix (ECM) hydrogels (Matrigel® or RegenixTM) and induced IPF-associated pathological features, including epithelial-mesenchymal transition (EMT), fibrosis, and inflammation. Parallel two-dimensional (2D) alveolar epithelial cultures were established for comparison. To examine multicellular contributions, organoids were co-cultured with human macrophages or fibroblasts, and expression of fibrosis (COL1A1, ACTA2), EMT (SNAI1, VIM), and inflammatory (TNF-α, IL-6) markers was analyzed using quantitative PCR and immunostaining. Compared with 2D cultures, lung organoids displayed stronger and more consistent expression of disease-relevant markers, capturing key IPF pathological features. Co-culture with fibroblasts enhanced fibrotic marker expression, whereas macrophage incorporation amplified inflammatory responses. Drug testing with clinically approved IPF therapeutics, Pirfenidone and Nintedanib, revealed dose-dependent effects, with organoids showing higher predictive accuracy than 2D cultures. Moreover, co-culture with macrophages or fibroblasts modulated drug sensitivity, highlighting the influence of multicellular interactions on therapeutic responses. Collectively, these findings demonstrate that human iPSC-derived lung organoids recapitulate IPF-associated cellular and molecular phenotypes more effectively than conventional 2D cultures. Incorporation of macrophages and fibroblasts provides a physiologically relevant microenvironment that improves disease modeling and enhances drug evaluation. This platform represents a robust and translatable system for studying IPF pathogenesis and screening candidate therapeutics, offering a valuable alternative to conventional models in translational research. This abstract is funded by: The Technology Innovation Program (20024298, Materials/Components Technology Development Program) funded by the Ministry of Trade, Industry & Energy(MOTIE, Korea)