@article{6bd01ca1876c45e39eede259d8dd03d4,
title = "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.",
keywords = "3D culture, airway organoids, cystic fibrosis, lung cancer, respiratory syncytial virus, PLURIPOTENT STEM-CELLS, CYSTIC-FIBROSIS, CHLORIDE CHANNEL, BASAL-CELLS, EPITHELIUM, REGENERATION, TARGET, GENERATION, DERIVATION, INHIBITION",
author = "Norman Sachs and Angelos Papaspyropoulos and {Zomer-van Ommen}, {Domenique D.} and Inha Heo and Lena Bottinger and Dymph Klay and Fleur Weeber and Guizela Huelsz-Prince and Nino Iakobachvili and Amatngalim, {Gimano D.} and {de Ligt}, Joep and {van Hoeck}, Arne and Natalie Proost and Viveen, {Marco C.} and Anna Lyubimova and Luc Teeven and Sepideh Derakhshan and Jeroen Korving and Harry Begthel and Dekkers, {Johanna F.} and Kuldeep Kumawat and Emilio Ramos and {van Oosterhout}, {Matthijs F. M.} and Offerhaus, {G. Johan} and Wiener, {Dominique J.} and Olimpio, {Eduardo P.} and Dijkstra, {Krijn K.} and Smit, {Egbert F.} and {van der Linden}, Maarten and Sridevi Jaksani and {van de Ven}, Marieke and Jos Jonkers and Rios, {Anne C.} and Voest, {Emile E.} and {van Moorsel}, {Coline H. M.} and {van der Ent}, {Cornelis K.} and Edwin Cuppen and {van Oudenaarden}, Alexander and Coenjaerts, {Frank E.} and Linde Meyaard and Bont, {Louis J.} and Peters, {Peter J.} and Tans, {Sander J.} and {van Zon}, {Jeroen S.} and Boj, {Sylvia F.} and Vries, {Robert G.} and Beekman, {Jeffrey M.} and Hans Clevers",
note = "Funding Information: We would like to acknowledge Carmen Lopez-Iglesias for supporting high-pressure freezing and freeze substitution. We thank Raimond Ravelli for providing transmission EM overview software and Antoni P.A. Hendrickx for help with scanning EM. We acknowledge Anko de Graaff and the Hubrecht Imaging Center for supporting light microscopy. We thank Inez Bronsveld for obtaining intestinal biopsies. We thank people from the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the NKI for performing the intervention studies. We acknowledge UBEC and USEQ. We thank the WKZ Pediatric Pulmonology Department for obtaining lavage fluid. We are grateful to Stieneke van den Brink and Nilofar Ehsani for preparing media. Genetically modified RSV variants were generously provided by Peter Collins, Mark E. Peeples, and Ulla Buchholz. We thank the Multiplex Core facility of the LTI UMC Utrecht for developing, validating, and performing immunoassays. Work at the Hubrecht Institute was supported by MKMD and VENI grants from the Dutch Organization of Scientific Research NWO (ZonMw 114021012 and 916.15.182), a Stand Up to Cancer International Translational Cancer Research Grant (a program of the Entertainment Industry Foundation administered by the AACR) and an Alpe d'Huze/KWF program grant (2014-7006). This work is part of the Oncode Institute which is partly financed by the Dutch Cancer Society and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO). The spinning disk microscope is funded by NWO equipment grant 834.11.002. Work in the laboratory of S.J.T. is part of the research program of the Foundation for Fundamental Research on Matter (FOM), as part of NWO. The work of G.H. and J.S.Z. was supported by a NWO VIDI grant (680-47-529) and a HFSP Career Development Award (CDA00076/2014-C). Work at the St. Antonius Hospital was supported by the Prof. Dr. Jaap Swierenga Foundation (development of human lung organoids). J.M.B., D.Z., and C.K.E. were supported by a grant from The Netherlands Organisation for Health Research and Development (ZonMW 40-00812-98-14103) and the Dutch Cystic Fibrosis Society (HIT-CF program). Funding Information: We would like to acknowledge Carmen Lopez-Iglesias for supporting high-pressure freezing and freeze substitution. We thank Raimond Ravelli for providing transmission EM overview software and Antoni P.A. Hendrickx for help with scanning EM. We acknowledge Anko de Graaff and the Hubrecht Imaging Center for supporting light microscopy. We thank Inez Bronsveld for obtaining intestinal biopsies. We thank people from the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the NKI for performing the intervention studies. We acknowledge UBEC and USEQ. We thank the WKZ Pediatric Pulmonology Department for obtaining lavage fluid. We are grateful to Stieneke van den Brink and Nilofar Ehsani for preparing media. Genetically modified RSV variants were generously provided by Peter Collins, Mark E. Peeples, and Ulla Buch-holz. We thank the Multiplex Core facility of the LTI UMC Utrecht for developing, validating, and performing immunoassays. Work at the Hubrecht Institute was supported by MKMD and VENI grants from the Dutch Organization of Scientific Research NWO (ZonMw 114021012 and 916.15.182), a Stand Up to Cancer International Translational Cancer Research Grant (a program of the Entertainment Industry Foundation administered by the AACR) and an Alpe d{\textquoteright}Huze/KWF program grant (2014-7006). This work is part of the Oncode Institute which is partly financed by the Dutch Cancer Society and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO). The spinning disk microscope is funded by NWO equipment grant 834.11.002. Work in the laboratory of S.J.T. is part of the research program of the Foundation for Fundamental Research on Matter (FOM), as part of NWO. The work of G.H. and J.S.Z. was supported by a NWO VIDI grant (680-47-529) and a HFSP Career Development Award (CDA00076/2014-C). Work at the St. Antonius Hospital was supported by the Prof. Dr. Jaap Swierenga Foundation (development of human lung organoids). J.M.B., D.Z., and C.K.E. were supported by a grant from The Netherlands Organisation for Health Research and Development (ZonMW 40-00812-98-14103) and the Dutch Cystic Fibrosis Society (HIT-CF program). Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2019",
month = feb,
day = "15",
doi = "10.15252/embj.2018100300",
language = "English",
volume = "38",
journal = "The Embo Journal",
issn = "0261-4189",
publisher = "Springer",
number = "4",
}