Abstract
SummaryAlthough alveolar epithelial cells play a critical role in the pathogenesis of pulmonary fibrosis, few practical in vitro models exist to study them. Here, we established a novel in vitro pulmonary fibrosis model using alveolar organoids consisting of human pluripotent stem cell-derived alveolar epithelial cells and primary human lung fibroblasts. In this human model, bleomycin treatment induced phenotypes such as epithelial cell-mediated fibroblast activation, cellular senescence, and presence of alveolar epithelial cells in abnormal differentiation states. Chemical screening performed to target these abnormalities showed that inhibition of ALK5 or blocking of integrin αVβ6 ameliorated the fibrogenic changes in the alveolar organoids. Furthermore, organoid contraction and extracellular matrix accumulation in the model recapitulated the pathological changes observed in pulmonary fibrosis. This human model may therefore accelerate the development of highly effective therapeutic agents for otherwise incurable pulmonary fibrosis by targeting alveolar epithelial cells and epithelial-mesenchymal interactions.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that is more likely to occur in the elderly
We previously reported a method of generating fibroblastdependent alveolar organoids (FD-AOs) from human pluripotent stem cells and primary human fetal lung fibroblasts (HFLFs) (Gotoh et al, 2014; Yamamoto et al, 2017)
Since FD-AOs were encapsulated in Matrigel, which is mainly composed of laminin, collagen, and a reduced amount of growth factors, we investigated whether fibroblast activation could cause contraction of the cultivation matrix
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that is more likely to occur in the elderly. Mutations in genes related to telomere homeostasis, such as TERT, TERC, PARN, and RTEL1, are associated with an increased risk of sporadic IPF (Lederer and Martinez, 2018). Aging, or at least cellular senescence, is believed to be involved in the onset of IPF. The pathogenesis of IPF is fundamentally based on initial alveolar epithelial injury followed by fibroblast activation (Katzen and Beers, 2020). Pirfenidone and nintedanib, the only two drugs for IPF approved by the US Food and Drug Administration, mainly target fibroblasts involved in the late stage of IPF (Spagnolo et al, 2020).
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