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We here established a three\u2010dimensional (3D) murine bronchioalveolar lung organoid (BALO) model that allows clonal expansion and self\u2010organization of FACS\u2010sorted bronchioalveolar stem cells (BASCs) upon co\u2010culture with lung\u2010resident mesenchymal cells. BALOs yield a highly branched 3D structure within 21\u00a0days of culture, mimicking the cellular composition of the bronchioalveolar compartment as defined by single\u2010cell RNA sequencing and fluorescence as well as electron microscopic phenotyping. Additionally, BALOs support engraftment and maintenance of the cellular phenotype of injected tissue\u2010resident 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\u2013mesenchymal\u2010myeloid unit of the distal lung, thereby opening numerous new avenues to study lung development, infection, and regenerative processes\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.15252\/embj.2019103476","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T09:08:12Z","timestamp":1601284092000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Multilineage murine stem cells generate complex organoids to model distal lung development and disease"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8498-6492","authenticated-orcid":false,"given":"Ana Ivonne","family":"Vazquez\u2010Armendariz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Heiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3417","authenticated-orcid":false,"given":"Elie","family":"El Agha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Salwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hoek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Christin","family":"Hessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Shalashova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Carraro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Philip","family":"Mengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0833-9749","authenticated-orcid":false,"given":"Rory Edward","family":"Morty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istv\u00e1n","family":"Vad\u00e1sz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-6855","authenticated-orcid":false,"given":"Martin","family":"Schwemmle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Kummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Hain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Goesmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-4804","authenticated-orcid":false,"given":"Thomas","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6343-0911","authenticated-orcid":false,"given":"Susanne","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"BFEMBJ2019103476_CR1","first-page":"4139","volume":"142","author":"D Al Alam","year":"2015","unstructured":"Al Alam D, El Agha E, Sakurai R, Kheirollahi V, Moiseenko A, Danopoulos S, Shrestha A, Schmoldt C, Quantius J, Herold S et\u00a0al (2015) Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. 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