Organoid model systems derived from mouse and human stem cells have recently evolved as a powerful tool to study development and disease. A murine 3D bronchioalveolar lung organoid model was established based on FACS-sorting of a newly defined population of bronchioalveolar stem cells. Upon co culture with subsets of lung mesenchymal cells, which model the stem cell niche of the developing lung, these stem cells underwent clonal expansion, followed by branching morphogenesis and self-organization into complete lung organoids, while retaining their tissue-of-origin commitment and their potential to differentiate into functional cells. Of note, organoids closely reproduced the 3D structure and cellular composition of the bronchioalveolar compartment of the lung. In addition, the 3D bronchioalveolar organoid structure allowed seeding of tissue-resident macrophages into the alveolar compartment, providing the possibility to study the contribution of the resident myeloid cell pool to developmental and regeneration processes within the alveolar microenvironment. Moreover, lung organoids derived from gene deficient mice and selective inhibitor experiments revealed that the GM CSF/GM-CSFR axis was necessary for BALO growth, survival, and alveolarization. Organoids were suitable for FACS-based single cell analyses, and for genetic manipulation as demonstrated by successful knockdown of genes involved in lung development and targeting miR142-3p/beta-catenin signaling. Finally, organoids could be used to model lung infection, as demonstrated by use of reporter-tagged influenza viruses in conjunction with live cell imaging, gene expression and functional analyses. In summary, this is the first organoid model recapitulating the 3D structure and cellular composition of the bronchioalveolar lung compartment, opening up new avenues to model lung development, infection, and regeneration processes.
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