Journal
EMBO JOURNAL
Volume 39, Issue 21, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019103476
Keywords
BALO; BASC; lung organoids; stem cells
Categories
Funding
- German Research Foundation (DFG) [SFB 1021 C05, Z02, SFB-TR84 B9, A6, KFO 309 P2/P5/P6/P7/P8/Z01, SFB 1160]
- German Research Foundation (Excellence Cluster Cardio Pulmonary System)
- University Hospital Giessen and Marburg (FOKOOPV)
- German Center for Lung Research (DZL)
- DFG [BE4443/4-1, BE4443/6-1, SFB1213]
- project A04 [SFB CRC1213]
- Institute for Lung Health (ILH)
- CardioPulmonary Institute (CPI) [EXC 2026, 390649896]
- BMBF [FKZ 031A533]
- Projekt DEAL
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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 processesin vitro.
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