Human alveolar progenitors generate dual lineage bronchioalveolar organoids

Hoffmann, Karen; Obermayer, Benedikt; Hoenzke, Katja; Fatykhova, Diana; Demir, Zeynep; Loewa, Anna; Alves, Luiz Gustavo Teixeira; Wyler, Emanuel; Lopez-Rodriguez, Elena; Mieth, Maren; Baumgardt, Morris; Hoope, Judith; Firsching, Theresa C.; Toennies, Mario; Bauer, Torsten T.; Eggeling, Stephan; Tran, Hong-Linh; Schneider, Paul; Neudecker, Jens; Rueckert, Jens C.; Gruber, Achim D.; Ochs, Matthias; Landthaler, Markus; Beule, Dieter; Suttorp, Norbert; Hippenstiel, Stefan; Hocke, Andreas C. und Kessler, Mirjana (2022): Human alveolar progenitors generate dual lineage bronchioalveolar organoids. In: Communications Biology, Bd. 5, Nr. 1, 875

Abstract

The GSK3 inhibitor CHIR99021 is required to maintain the alveolar lineage in alveolar progenitors grown in airway media or AT2 cells become plastic, with the observed effects acting outside of its role as a GSK3B inhibitor. Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280(+)/EpCAM(+) population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3 beta inhibitor, CHIR99021. By RNA-seq profiling of GSK-3 beta knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch