Organoids derived from mouse and human stem cells have recently emerged as a powerful tool to study organ development and disease. We here established a three-dimensional (3D) murine bronchioalveolar lung organoid (BALO) model that allows clonal expansion and self-organization of FACS-sorted bronchioalveolar stem cells (BASCs) upon co-culture with lung-resident mesenchymal cells. BALOs yield a highly branched 3D structure within 21 days of culture, mimicking the cellular composition of the bronchioalveolar compartment as defined by single-cell RNA sequencing and fluorescence as well as electron microscopic phenotyping. Additionally, BALOs support engraftment and maintenance of the cellular phenotype of injected tissue-resident macrophages. We also demonstrate that BALOs recapitulate lung developmental defects after knockdown of a critical regulatory gene, and permit modeling of viral infection. We conclude that the BALO model enables reconstruction of the epithelial-mesenchymal-myeloid unit of the distal lung, thereby opening numerous new avenues to study lung development, infection, and regenerative processes in vitro.
- Vazquez-Armendariz, A. I.
- Heiner, M.
- El Agha, E.
- Salwig, I.
- Hoek, A.
- Hessler, M. C.
- Shalashova, I.
- Shrestha, A.
- Carraro, G.
- Mengel, J. P.
- Günther, A.
- Morty, R. E.
- Vadász, I.
- Schwemmle, M.
- Kummer, W.
- Hain, T.
- Goesmann, A.
- Bellusci, S.
- Seeger, W.
- Braun, T.
- Herold, S.
Keywords
- Balo
- Basc
- lung organoids
- stem cells
