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Long-term expanding human airway organoids for disease modeling.

ABSTRACT: Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

SUBMITTER: Sachs N

PROVIDER: S-EPMC6376275 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Long-term expanding human airway organoids for disease modeling.

Sachs Norman N Papaspyropoulos Angelos A Zomer-van Ommen Domenique D DD Heo Inha I Böttinger Lena L Klay Dymph D Weeber Fleur F Huelsz-Prince Guizela G Iakobachvili Nino N Amatngalim Gimano D GD de Ligt Joep J van Hoeck Arne A Proost Natalie N Viveen Marco C MC Lyubimova Anna A Teeven Luc L Derakhshan Sepideh S Korving Jeroen J Begthel Harry H Dekkers Johanna F JF Kumawat Kuldeep K Ramos Emilio E van Oosterhout Matthijs Fm MF Offerhaus G Johan GJ Wiener Dominique J DJ Olimpio Eduardo P EP Dijkstra Krijn K KK Smit Egbert F EF van der Linden Maarten M Jaksani Sridevi S van de Ven Marieke M Jonkers Jos J Rios Anne C AC Voest Emile E EE van Moorsel Coline Hm CH van der Ent Cornelis K CK Cuppen Edwin E van Oudenaarden Alexander A Coenjaerts Frank E FE Meyaard Linde L Bont Louis J LJ Peters Peter J PJ Tans Sander J SJ van Zon Jeroen S JS Boj Sylvia F SF Vries Robert G RG Beekman Jeffrey M JM Clevers Hans H

The EMBO journal 20190114 4

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow asse ...[more]

PMID: 30643021

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Project description:Respiratory coronaviruses cause serious health threats to humans and animals. Porcine respiratory coronavirus (PRCoV), a natural transmissible gastroenteritis virus (TGEV) mutant with partial spike deletion, causes mild respiratory disease and is an interesting animal respiratory coronavirus model for human respiratory coronaviruses. However, the absence of robust ex vivo models of porcine airway epithelium hinders an understanding of the pathogenesis of PRCoV infection. Here, we generated long-term porcine airway organoids (AOs) derived from basal epithelial cells, which recapitulate the in vivo airway complicated epithelial cellularity. Both 3D and 2D AOs are permissive for PRCoV infection. Unlike TGEV, which established successful infection in both AOs and intestinal organoids, PRCoV was strongly amplified only in AOs, not intestinal organoids. Furthermore, PRCoV infection in AOs mounted vigorous early type I and III interferon (IFN) responses and upregulated the expression of overzealous inflammatory genes, including pattern recognition receptors (PRRs) and proinflammatory cytokines. Collectively, these data demonstrate that stem-derived porcine AOs can serve as a promising disease model for PRCoV infection and provide a valuable tool to study porcine respiratory infection. IMPORTANCE Porcine respiratory CoV (PRCoV), a natural mutant of TGEV, shows striking pathogenetic similarities to human respiratory CoV infection and provides an interesting animal model for human respiratory CoVs, including SARS-CoV-2. The lack of an in vitro model recapitulating the complicated cellularity and structure of the porcine respiratory tract is a major roadblock for the study of PRCoV infection. Here, we developed long-term 3D airway organoids (AOs) and further established 2D AO monolayer cultures. The resultant 3D and 2D AOs are permissive for PRCoV infection. Notably, PRCoV mediated pronounced IFN and inflammatory responses in AOs, which recapitulated the inflammatory responses associated with PRCoV in vivo infection. Therefore, porcine AOs can be utilized to characterize the pathogenesis of PRCoV and, more broadly, can serve as a universal platform for porcine respiratory infection.

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Long-term expanding human airway organoids for disease modeling.

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Long-term expanding human airway organoids for disease modeling.

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