Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modelling, drug discovery and regenerative medicine1. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants2, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs3. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis4,5, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.
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This work was supported by grant NIH HL120046-01 (H.-W.S.), 1U01HL134760-01 (H.-W.S.) RO1 AI031971 (A.M.), and RO1 AI114736 (A.M.), as well as a sponsored research and agreement from Northern Biologics Inc. (H.-W.S.), and funding from the Thomas R Kully IPF Research Fund (H.-W.S.). RUES2-HPS1 cells were generated by the Columbia Stem Cell Core Facility. We thank NYULMC OCS Microscopy core C. Petzold and K. Dancel for their assistance with transmission electron microscopy. We thank M. Peeples (Ohio State University) for providing the original recombinant RSV. Flow cytometry was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10RR027050 and S10OD020056.
Integrated supplementary information
Bright field movie showing beating cilia in LBO-derived growth (RUES2) 5 months after engraftment. Section was made using a vibratome. Scale bar 75 μm.
Bright field movie showing the connected dilated saccules and structures resembling pulmonary acini in C12 LBOs. Scale bar 100 μm.
Time lapse movie of several distal buds of different d170 LBOs (RUES2) taken at 2 min intervals. The movie shows uptake of SPB-BODIPY over time in the cells and secretion into the lumen. Green: SPB-BODIPY. Scale bar 50 μm.
Confocal microscopy movie of a distal bud of a d170 LBO (RUES2) showing infected cells in the lumen (RSV antigen, green; DAPI, blue). Scale bar 50 μm.
About this article
Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine
Experimental Hematology & Oncology (2018)