Pulmonary fibrosis model using micro-CT analyzable human PSC–derived alveolar organoids containing alveolar macrophage-like cells

• Published in: Cell biology and toxicology Vol. 38; no. 4; pp. 557 - 575
• Main Authors: Choi, Seri, Choi, Jiwoong, Cheon, Seongmin, Song, Jihong, Kim, Seung-Yeon, Kim, Ji-eun, Nam, Dae-Hwan, Manzar, Gohar, Kim, Su-Man, Kang, Hyung-Sik, Kim, Kee K., Jeong, Sang Hoon, Lee, Ju-Han, Park, Eun-Kee, Lee, Minseob, Lee, Hyang-Ae, Kim, Ki-Suk, Park, Han-Jin, Oh, Won Keun, Park, Chungoo, Lee, Chang Hyun, Kim, Eun-Mi
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2022; Springer Nature B.V
• Subjects: Alveoli; Biochemistry; Biocompatibility; Biomarkers; Biomedical and Life Sciences; Bleomycin; Cell Biology; Computed tomography; Coronaviruses; Disease; Drug screening; Embryos; Epithelial cells; Epithelium; Extracellular matrix; Fibrosis; Hospitals; Image acquisition; Immune system; Internal medicine; Life Sciences; Lung diseases; Lungs; Macrophages; Medical schools; Medicine; Organoids; Original; Original Article; Pharmacology/Toxicology; Physiology; Pluripotency; Pulmonary fibrosis; Stem cells; Tomography; Toxicity; Toxicology; University colleges; Micro-CT; Fibrosis model; Human alveolar organoid; Alveolar macrophage
• ISSN: 0742-2091; 1573-6822
• DOI: 10.1007/s10565-022-09698-1

Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)–like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68 + AMφ-like cells were spatially organized on the luminal epithelial surface of alveolar hLOs. Bleomycin-treated alveolar hLOs showed upregulated expression of fibrosis-related markers and extracellular matrix deposits in the alveolar sacs. Alveolar hLOs also showed structural alterations such as excessive tissue fraction under bleomycin treatment. Therefore, we suggest that micro-CT analyzable PSC-derived alveolar hLOs are a promising in vitro model to predict lung toxicity manifestations, including fibrosis. Graphical abstract