Human pluripotent stem cell‐derived lung organoids: Potential applications in development and disease modeling

Advanced Review

Lu Tian, Jinghui Gao, Irving M. Garcia, Huanhuan Joyce Chen, Alessandra Castaldi, Ya‐Wen Chen

Published Online: Nov 04 2020

DOI: 10.1002/wdev.399

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Abstract The pulmonary system is comprised of two main compartments, airways and alveolar space. Their tissue and cellular complexity ensure lung function and protection from external agents, for example, virus. Two‐dimensional (2D) in vitro systems and animal models have been largely employed to elucidate the molecular mechanisms underlying human lung development, physiology, and pathogenesis. However, neither of these models accurately recapitulate the human lung environment and cellular crosstalk. More recently, human‐derived three‐dimensional (3D) models have been generated allowing for a deeper understanding of cell‐to‐cell communication. However, the availability and accessibility of primary human cell sources from which generate the 2D and 3D models may be limited. In the past few years, protocols have been developed to successfully employ human pluripotent stem cells (hPSCs) and differentiate them toward pulmonary fate in vitro. In the present review, we discuss the advantages and pitfalls of hPSC‐derived lung 2D and 3D models, including the main characteristics and potentials for these models and their current and future applications for modeling development and diseases. Lung organoids currently represent the closest model to the human pulmonary system. We further focus on the applications of lung organoids for the study of human diseases such as pulmonary fibrosis, infectious diseases, and lung cancer. Finally, we discuss the present limitations and potential future applications of 3D lung organoids. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion

Current in vitro models of human lung and their applications

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References

Arrowsmith,, J. (2011). Trial watch: Phase II failures: 2008‐2010. Nature Reviews. Drug Discovery, 10(5), 328–329. https://doi.org/10.1038/nrd3439
Barkauskas,, C. E., Cronce,, M. J., Rackley,, C. R., Bowie,, E. J., Keene,, D. R., Stripp,, B. R., … Hogan,, B. L. (2013). Type 2 alveolar cells are stem cells in adult lung. The Journal of Clinical Investigation, 123(7), 3025–3036. https://doi.org/10.1172/JCI68782
Bellusci,, S., Furuta,, Y., Rush,, M. G., Henderson,, R., Winnier,, G., & Hogan,, B. L. (1997). Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development, 124(1), 53–63 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9006067
Benali,, R., Chevillard,, M., Zahm,, J. M., Hinnrasky,, J., Klossek,, J. M., & Puchelle,, E. (1992). Tubule formation and functional differentiation by human epithelial respiratory cells cultured in a three‐dimensional collagen matrix. Chest, 101(3 Suppl), 7S–9S. https://doi.org/10.1378/chest.101.3_supplement.7s
Burri,, P. H. (1984). Fetal and postnatal development of the lung. Annual Review of Physiology, 46, 617–628. https://doi.org/10.1146/annurev.ph.46.030184.003153
Butler,, C. R., Hynds,, R. E., Gowers,, K. H., Lee Ddo,, H., Brown,, J. M., Crowley,, C., … Janes,, S. M. (2016). Rapid expansion of human epithelial stem cells suitable for airway tissue engineering. American Journal of Respiratory and Critical Care Medicine, 194(2), 156–168. https://doi.org/10.1164/rccm.201507-1414OC
Cai,, J., Zhao,, Y., Liu,, Y., Ye,, F., Song,, Z., Qin,, H., … Deng,, H. (2007). Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology, 45(5), 1229–1239. https://doi.org/10.1002/hep.21582
Cancer Genome Atlas Research, N. (2012). Comprehensive genomic characterization of squamous cell lung cancers. Nature, 489(7417), 519–525. https://doi.org/10.1038/nature11404
Cancer Genome Atlas Research, N. (2014). Comprehensive molecular profiling of lung adenocarcinoma. Nature, 511(7511), 543–550. https://doi.org/10.1038/nature13385
Cardoso,, W. V., & Lu,, J. (2006). Regulation of early lung morphogenesis: Questions, facts and controversies. Development, 133(9), 1611–1624. https://doi.org/10.1242/dev.02310
Chen,, H. J., Poran,, A., Unni,, A. M., Huang,, S. X., Elemento,, O., Snoeck,, H. W., & Varmus,, H. (2019). Generation of pulmonary neuroendocrine cells and SCLC‐like tumors from human embryonic stem cells. The Journal of Experimental Medicine, 216(3), 674–687. https://doi.org/10.1084/jem.20181155
Chen,, N., Zhou,, M., Dong,, X., Qu,, J., Gong,, F., Han,, Y., … Zhang,, L. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet, 395(10223), 507–513. https://doi.org/10.1016/S0140-6736(20)30211-7
Chen,, Y. W., Ahmed,, A., & Snoeck,, H. W. (2017). Generation of three‐dimensional lung bud organoid and its derived branching colonies. Protocol Exchange. https://doi.org/10.1038/protex.2017.027
Chen,, Y. W., Huang,, S. X., de Carvalho,, A., Ho,, S. H., Islam,, M. N., Volpi,, S., … Snoeck,, H. W. (2017). A three‐dimensional model of human lung development and disease from pluripotent stem cells. Nature Cell Biology, 19(5), 542–549. https://doi.org/10.1038/ncb3510
Cheng,, T. Y., Cramb,, S. M., Baade,, P. D., Youlden,, D. R., Nwogu,, C., & Reid,, M. E. (2016). The international epidemiology of lung cancer: Latest trends, disparities, and tumor characteristics. Journal of Thoracic Oncology, 11(10), 1653–1671. https://doi.org/10.1016/j.jtho.2016.05.021
Choi,, J., Iich,, E., & Lee,, J. H. (2016). Organogenesis of adult lung in a dish: Differentiation, disease and therapy. Developmental Biology, 420(2), 278–286. https://doi.org/10.1016/j.ydbio.2016.10.002
Clevers,, H. (2016). Modeling development and disease with organoids. Cell, 165(7), 1586–1597. https://doi.org/10.1016/j.cell.2016.05.082
Collins,, P. L., Fearns,, R., & Graham,, B. S. (2013). Respiratory syncytial virus: Virology, reverse genetics, and pathogenesis of disease. Current Topics in Microbiology and Immunology, 372, 3–38. https://doi.org/10.1007/978-3-642-38919-1_1
D`Amour,, K. A., Bang,, A. G., Eliazer,, S., Kelly,, O. G., Agulnick,, A. D., Smart,, N. G., … Baetge,, E. E. (2006). Production of pancreatic hormone‐expressing endocrine cells from human embryonic stem cells. Nature Biotechnology, 24(11), 1392–1401. https://doi.org/10.1038/nbt1259
Danahay,, H., Pessotti,, A. D., Coote,, J., Montgomery,, B. E., Xia,, D., Wilson,, A., … Jaffe,, A. B. (2015). Notch2 is required for inflammatory cytokine‐driven goblet cell metaplasia in the lung. Cell Reports, 10(2), 239–252. https://doi.org/10.1016/j.celrep.2014.12.017
Desai,, T. J., Brownfield,, D. G., & Krasnow,, M. A. (2014). Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature, 507(7491), 190–194. https://doi.org/10.1038/nature12930
Dijkstra,, K. K., Monkhorst,, K., Schipper,, L. J., Hartemink,, K. J., Smit,, E. F., Kaing,, S., … Voest,, E. E. (2020). Challenges in establishing pure lung cancer organoids limit their utility for personalized medicine. Cell Reports, 31(5), 107588. https://doi.org/10.1016/j.celrep.2020.107588
Dye,, B. R., Dedhia,, P. H., Miller,, A. J., Nagy,, M. S., White,, E. S., Shea,, L. D., & Spence,, J. R. (2016). A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. eLife, 5, e19732. https://doi.org/10.7554/eLife.19732
Dye,, B. R., Hill,, D. R., Ferguson,, M. A., Tsai,, Y. H., Nagy,, M. S., Dyal,, R., … Spence,, J. R. (2015). In vitro generation of human pluripotent stem cell derived lung organoids. eLife, 4, e05098. https://doi.org/10.7554/eLife.05098
Finkbeiner,, S. R., Hill,, D. R., Altheim,, C. H., Dedhia,, P. H., Taylor,, M. J., Tsai,, Y. H., … Spence,, J. R. (2015). Transcriptome‐wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo. Stem Cell Reports, 4, 1140–1155. https://doi.org/10.1016/j.stemcr.2015.04.010
George,, J., Lim,, J. S., Jang,, S. J., Cun,, Y., Ozretic,, L., Kong,, G., … Thomas,, R. K. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524(7563), 47–53. https://doi.org/10.1038/nature14664
Gotoh,, S., Ito,, I., Nagasaki,, T., Yamamoto,, Y., Konishi,, S., Korogi,, Y., … Mishima,, M. (2014). Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. Stem Cell Reports, 3(3), 394–403. https://doi.org/10.1016/j.stemcr.2014.07.005
Gouon‐Evans,, V., Boussemart,, L., Gadue,, P., Nierhoff,, D., Koehler,, C. I., Kubo,, A., … Keller,, G. (2006). BMP‐4 is required for hepatic specification of mouse embryonic stem cell‐derived definitive endoderm. Nature Biotechnology, 24(11), 1402–1411. https://doi.org/10.1038/nbt1258
Green,, M. D., Chen,, A., Nostro,, M. C., d`Souza,, S. L., Schaniel,, C., Lemischka,, I. R., … Snoeck,, H. W. (2011). Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nature Biotechnology, 29(3), 267–272. https://doi.org/10.1038/nbt.1788
Hanna,, J. M., & Onaitis,, M. W. (2013). Cell of origin of lung cancer. Journal of Carcinogenesis, 12, 6. https://doi.org/10.4103/1477-3163.109033
Hawkins,, F., Kramer,, P., Jacob,, A., Driver,, I., Thomas,, D. C., McCauley,, K. B., … Kotton,, D. N. (2017). Prospective isolation of NKX2‐1‐expressing human lung progenitors derived from pluripotent stem cells. The Journal of Clinical Investigation, 127(6), 2277–2294. https://doi.org/10.1172/JCI89950
Hegab,, A. E., Ha,, V. L., Darmawan,, D. O., Gilbert,, J. L., Ooi,, A. T., Attiga,, Y. S., … Gomperts,, B. N. (2012). Isolation and in vitro characterization of basal and submucosal gland duct stem/progenitor cells from human proximal airways. Stem Cells Translational Medicine, 1(10), 719–724. https://doi.org/10.5966/sctm.2012-0056
Herbst,, R. S., Heymach,, J. V., & Lippman,, S. M. (2008). Lung cancer. The New England Journal of Medicine, 359(13), 1367–1380. https://doi.org/10.1056/NEJMra0802714
Herriges,, M., & Morrisey,, E. E. (2014). Lung development: Orchestrating the generation and regeneration of a complex organ. Development, 141(3), 502–513. https://doi.org/10.1242/dev.098186
Hild,, M., & Jaffe,, A. B. (2016). Production of 3‐D airway organoids from primary human airway basal cells and their use in high‐throughput screening. Current Protocols in Stem Cell Biology, 37, IE 9 1–IE 9 15. https://doi.org/10.1002/cpsc.1
Huang,, S. X., Green,, M. D., de Carvalho,, A. T., Mumau,, M., Chen,, Y. W., D`Souza,, S. L., & Snoeck,, H. W. (2015). The in vitro generation of lung and airway progenitor cells from human pluripotent stem cells. Nature Protocols, 10(3), 413–425. https://doi.org/10.1038/nprot.2015.023
Huang,, S. X., Islam,, M. N., O`Neill,, J., Hu,, Z., Yang,, Y. G., Chen,, Y. W., … Snoeck,, H. W. (2014). Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nature Biotechnology, 32(1), 84–91. https://doi.org/10.1038/nbt.2754
Hughes,, C. S., Postovit,, L. M., & Lajoie,, G. A. (2010). Matrigel: A complex protein mixture required for optimal growth of cell culture. Proteomics, 10(9), 1886–1890. https://doi.org/10.1002/pmic.200900758
Jacob,, A., Morley,, M., Hawkins,, F., McCauley,, K. B., Jean,, J. C., Heins,, H., … Kotton,, D. N. (2017). Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell, 21(4), 472–488 e410. https://doi.org/10.1016/j.stem.2017.08.014
Kim,, M., Mun,, H., Sung,, C. O., Cho,, E. J., Jeon,, H. J., Chun,, S. M., … Jang,, S. J. (2019). Patient‐derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nature Communications, 10(1), 3991. https://doi.org/10.1038/s41467-019-11867-6
King,, T. E., Jr., Bradford,, W. Z., Castro‐Bernardini,, S., Fagan,, E. A., Glaspole,, I., Glassberg,, M. K., … Group, A. S. (2014). A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England Journal of Medicine, 370(22), 2083–2092. https://doi.org/10.1056/NEJMoa1402582
Konishi,, S., Gotoh,, S., Tateishi,, K., Yamamoto,, Y., Korogi,, Y., Nagasaki,, T., … Mishima,, M. (2016). Directed induction of functional multi‐ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. Stem Cell Reports, 6(1), 18–25. https://doi.org/10.1016/j.stemcr.2015.11.010
Lancaster,, M. A., & Huch,, M. (2019). Disease modelling in human organoids. Disease Models %26 Mechanisms, 12(7), dmm039347. https://doi.org/10.1242/dmm.039347
Lancaster,, M. A., & Knoblich,, J. A. (2014). Organogenesis in a dish: Modeling development and disease using organoid technologies. Science, 345(6194), 1247125. https://doi.org/10.1126/science.1247125
Lancaster,, M. A., Renner,, M., Martin,, C. A., Wenzel,, D., Bicknell,, L. S., Hurles,, M. E., … Knoblich,, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373–379. https://doi.org/10.1038/nature12517
Lederer,, D. J., & Martinez,, F. J. (2018). Idiopathic pulmonary fibrosis. The New England Journal of Medicine, 379(8), 797–798. https://doi.org/10.1056/NEJMc1807508
Lee,, H. W., Lee,, C. H., & Park,, Y. S. (2018). Location of stage I‐III non‐small cell lung cancer and survival rate: Systematic review and meta‐analysis. Thoracic Cancer, 9(12), 1614–1622. https://doi.org/10.1111/1759-7714.12869
Lee,, J. H., Bhang,, D. H., Beede,, A., Huang,, T. L., Stripp,, B. R., Bloch,, K. D., … Kim,, C. F. (2014). Lung stem cell differentiation in mice directed by endothelial cells via a BMP4‐NFATc1‐thrombospondin‐1 axis. Cell, 156(3), 440–455. https://doi.org/10.1016/j.cell.2013.12.039
Li,, M., & Izpisua Belmonte,, J. C. (2019). Organoids—Preclinical models of human disease. New England Journal of Medicine, 380(6), 569–579. https://doi.org/10.1056/NEJMra1806175
McCauley,, K. B., Hawkins,, F., Serra,, M., Thomas,, D. C., Jacob,, A., & Kotton,, D. N. (2017). Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of Wnt Signaling. Cell Stem Cell, 20(6), 844–857 e846. https://doi.org/10.1016/j.stem.2017.03.001
McCracken,, K. W., Cata,, E. M., Crawford,, C. M., Sinagoga,, K. L., Schumacher,, M., Rockich,, B. E., … Wells,, J. M. (2014). Modelling human development and disease in pluripotent stem‐cell‐derived gastric organoids. Nature, 516(7531), 400–404. https://doi.org/10.1038/nature13863
McCurry,, K. R., Shearon,, T. H., Edwards,, L. B., Chan,, K. M., Sweet,, S. C., Valapour,, M., … Murray,, S. (2009). Lung transplantation in the United States, 1998‐2007. American Journal of Transplantation, 9(4 Pt 2), 942–958. https://doi.org/10.1111/j.1600-6143.2009.02569.x
Miller,, A. J., Dye,, B. R., Ferrer‐Torres,, D., Hill,, D. R., Overeem,, A. W., Shea,, L. D., & Spence,, J. R. (2019). Generation of lung organoids from human pluripotent stem cells in vitro. Nature Protocols, 14(2), 518–540. https://doi.org/10.1038/s41596-018-0104-8
Miller, A. J., Hill, D. R., Nagy, M. S., Aoki, Y., Dye, B. R., Chin, A. M., … Spence, J. R. (2018). In vitro induction and in vivo engraftment of lung bud tip progenitor cells derived from human pluripotent stem cells. Stem Cell Reports, 10(1), 101–119. https://doi.org/10.1016/j.stemcr.2017.11.012
Morrisey,, E. E., & Hogan,, B. L. (2010). Preparing for the first breath: Genetic and cellular mechanisms in lung development. Developmental Cell, 18(1), 8–23. https://doi.org/10.1016/j.devcel.2009.12.010
Mou,, H., Vinarsky,, V., Tata,, P. R., Brazauskas,, K., Choi,, S. H., Crooke,, A. K., … Rajagopal,, J. (2016). Dual SMAD signaling inhibition enables long‐term expansion of diverse epithelial basal cells. Cell Stem Cell, 19(2), 217–231. https://doi.org/10.1016/j.stem.2016.05.012
Mou,, H., Zhao,, R., Sherwood,, R., Ahfeldt,, T., Lapey,, A., Wain,, J., … Rajagopal,, J. (2012). Generation of multipotent lung and airway progenitors from mouse ESCs and patient‐specific cystic fibrosis iPSCs. Cell Stem Cell, 10(4), 385–397. https://doi.org/10.1016/j.stem.2012.01.018
Munera,, J. O., Sundaram,, N., Rankin,, S. A., Hill,, D., Watson,, C., Mahe,, M., … Wells,, J. M. (2017). Differentiation of human pluripotent stem cells into colonic organoids via transient activation of BMP signaling. Cell Stem Cell, 21(1), 51–64 e56. https://doi.org/10.1016/j.stem.2017.05.020
Murry,, C. E., & Keller,, G. (2008). Differentiation of embryonic stem cells to clinically relevant populations: Lessons from embryonic development. Cell, 132(4), 661–680. https://doi.org/10.1016/j.cell.2008.02.008
Nakano,, T., Ando,, S., Takata,, N., Kawada,, M., Muguruma,, K., Sekiguchi,, K., … Sasai,, Y. (2012). Self‐formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell, 10(6), 771–785. https://doi.org/10.1016/j.stem.2012.05.009
Neuberger,, T., Burton,, B., Clark,, H., & Van Goor,, F. (2011). Use of primary cultures of human bronchial epithelial cells isolated from cystic fibrosis patients for the pre‐clinical testing of CFTR modulators. Methods in Molecular Biology, 741, 39–54. https://doi.org/10.1007/978-1-61779-117-8_4
Nikolic,, M. Z., Caritg,, O., Jeng,, Q., Johnson,, J. A., Sun,, D., Howell,, K. J., … Rawlins,, E. L. (2017). Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long‐term self‐renewing organoids. eLife, 6, e26575. https://doi.org/10.7554/eLife.26575
Nikolic,, M. Z., Sun,, D., & Rawlins,, E. L. (2018). Human lung development: Recent progress and new challenges. Development, 145(16), dev163485. https://doi.org/10.1242/dev.163485
Noble,, P. W., Barkauskas,, C. E., & Jiang,, D. (2012). Pulmonary fibrosis: Patterns and perpetrators. The Journal of Clinical Investigation, 122(8), 2756–2762. https://doi.org/10.1172/JCI60323
Pang,, Z. P., Yang,, N., Vierbuchen,, T., Ostermeier,, A., Fuentes,, D. R., Yang,, T. Q., … Wernig,, M. (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476(7359), 220–223. https://doi.org/10.1038/nature10202
Poirier,, J. T., George,, J., Owonikoko,, T. K., Berns,, A., Brambilla,, E., Byers,, L. A., … Oliver,, T. G. (2020). New approaches to SCLC therapy: From the laboratory to the clinic. Journal of Thoracic Oncology, 15(4), 520–540. https://doi.org/10.1016/j.jtho.2020.01.016
Porotto,, M., Ferren,, M., Chen,, Y. W., Siu,, Y., Makhsous,, N., Rima,, B., … Moscona,, A. (2019). Authentic modeling of human respiratory virus infection in human pluripotent stem cell‐derived lung organoids. MBio, 10(3), e00723‐19. https://doi.org/10.1128/mBio.00723-19
Quadrato,, G., Nguyen,, T., Macosko,, E. Z., Sherwood,, J. L., Min Yang,, S., Berger,, D. R., … Arlotta,, P. (2017). Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 545(7652), 48–53. https://doi.org/10.1038/nature22047
Rawlins,, E. L., Okubo,, T., Xue,, Y., Brass,, D. M., Auten,, R. L., Hasegawa,, H., … Hogan,, B. L. (2009). The role of Scgb1a1+ Clara cells in the long‐term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell, 4(6), 525–534. https://doi.org/10.1016/j.stem.2009.04.002
Richeldi,, L., du Bois,, R. M., Raghu,, G., Azuma,, A., Brown,, K. K., Costabel,, U., … Investigators,, I. T. (2014). Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England Journal of Medicine, 370(22), 2071–2082. https://doi.org/10.1056/NEJMoa1402584
Rock,, J. R., Onaitis,, M. W., Rawlins,, E. L., Lu,, Y., Clark,, C. P., Xue,, Y., … Hogan,, B. L. (2009). Basal cells as stem cells of the mouse trachea and human airway epithelium. Proceedings of the National Academy of Sciences of the United States of America, 106(31), 12771–12775. https://doi.org/10.1073/pnas.0906850106
Rock,, J. R., Randell,, S. H., & Hogan,, B. L. (2010). Airway basal stem cells: A perspective on their roles in epithelial homeostasis and remodeling. Disease Models %26 Mechanisms, 3(9–10), 545–556. https://doi.org/10.1242/dmm.006031
Ryu,, J. H., Moua,, T., Daniels,, C. E., Hartman,, T. E., Yi,, E. S., Utz,, J. P., & Limper,, A. H. (2014). Idiopathic pulmonary fibrosis: Evolving concepts. Mayo Clinic Proceedings, 89(8), 1130–1142. https://doi.org/10.1016/j.mayocp.2014.03.016
Sachs,, N., Papaspyropoulos,, A., Zomer‐van Ommen,, D. D., Heo,, I., Bottinger,, L., Klay,, D., … Clevers,, H. (2019). Long‐term expanding human airway organoids for disease modeling. The EMBO Journal, 38(4), e100300. https://doi.org/10.15252/embj.2018100300
Schier,, A. F. (2003). Nodal signaling in vertebrate development. Annual Review of Cell and Developmental Biology, 19, 589–621. https://doi.org/10.1146/annurev.cellbio.19.041603.094522
Schwank,, G., Koo,, B. K., Sasselli,, V., Dekkers,, J. F., Heo,, I., Demircan,, T., … Clevers,, H. (2013). Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell, 13(6), 653–658. https://doi.org/10.1016/j.stem.2013.11.002
Shanks,, N., Greek,, R., & Greek,, J. (2009). Are animal models predictive for humans? Philosophy, Ethics, and Humanities in Medicine, 4, 2. https://doi.org/10.1186/1747-5341-4-2
Shi,, R., Radulovich,, N., Ng,, C., Liu,, N., Notsuda,, H., Cabanero,, M., … Tsao,, M. S. (2020). Organoid cultures as preclinical models of non‐small cell Lung cancer. Clinical Cancer Research, 26(5), 1162–1174. https://doi.org/10.1158/1078-0432.CCR-19-1376
Shi,, Y., Desponts,, C., Do,, J. T., Hahm,, H. S., Scholer,, H. R., & Ding,, S. (2008). Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small‐molecule compounds. Cell Stem Cell, 3(5), 568–574. https://doi.org/10.1016/j.stem.2008.10.004
Simian,, M., & Bissell,, M. J. (2017). Organoids: A historical perspective of thinking in three dimensions. The Journal of Cell Biology, 216(1), 31–40. https://doi.org/10.1083/jcb.201610056
Smith,, E., & Cochrane,, W. J. (1946). Cystic organoid teratoma: Report of a case. Canadian Medical Association Journal, 55(2), 151 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20992760
Spence,, J. R., Mayhew,, C. N., Rankin,, S. A., Kuhar,, M. F., Vallance,, J. E., Tolle,, K., … Wells,, J. M. (2011). Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature, 470(7332), 105–109. https://doi.org/10.1038/nature09691
Stainier,, D. Y. (2002). A glimpse into the molecular entrails of endoderm formation. Genes %26 Development, 16(8), 893–907. https://doi.org/10.1101/gad.974902
Strikoudis,, A., Cieslak,, A., Loffredo,, L., Chen,, Y. W., Patel,, N., Saqi,, A., … Snoeck,, H. W. (2019). Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells. Cell Reports, 27(12), 3709–3723 e3705. https://doi.org/10.1016/j.celrep.2019.05.077
Sutherland,, K. D., & Berns,, A. (2010). Cell of origin of lung cancer. Molecular Oncology, 4(5), 397–403. https://doi.org/10.1016/j.molonc.2010.05.002
Sutherland,, K. D., Proost,, N., Brouns,, I., Adriaensen,, D., Song,, J. Y., & Berns,, A. (2011). Cell of origin of small cell lung cancer: Inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell, 19(6), 754–764. https://doi.org/10.1016/j.ccr.2011.04.019
Swarr,, D. T., & Morrisey,, E. E. (2015). Lung endoderm morphogenesis: Gasping for form and function. Annual Review of Cell and Developmental Biology, 31, 553–573. https://doi.org/10.1146/annurev-cellbio-100814-125249
Szabo,, M., Svensson Akusjarvi,, S., Saxena,, A., Liu,, J., Chandrasekar,, G., & Kitambi,, S. S. (2017). Cell and small animal models for phenotypic drug discovery. Drug Design, Development and Therapy, 11, 1957–1967. https://doi.org/10.2147/DDDT.S129447
Taguchi,, A., Kaku,, Y., Ohmori,, T., Sharmin,, S., Ogawa,, M., Sasaki,, H., & Nishinakamura,, R. (2014). Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell, 14(1), 53–67. https://doi.org/10.1016/j.stem.2013.11.010
Takahashi,, K., & Yamanaka,, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024
Takasato,, M., Er,, P. X., Becroft,, M., Vanslambrouck,, J. M., Stanley,, E. G., Elefanty,, A. G., & Little,, M. H. (2014). Directing human embryonic stem cell differentiation towards a renal lineage generates a self‐organizing kidney. Nature Cell Biology, 16(1), 118–126. https://doi.org/10.1038/ncb2894
Takebe,, T., Sekine,, K., Enomura,, M., Koike,, H., Kimura,, M., Ogaeri,, T., … Taniguchi,, H. (2013). Vascularized and functional human liver from an iPSC‐derived organ bud transplant. Nature, 499(7459), 481–484. https://doi.org/10.1038/nature12271
Tam,, P. P., Kanai‐Azuma,, M., & Kanai,, Y. (2003). Early endoderm development in vertebrates: Lineage differentiation and morphogenetic function. Current Opinion in Genetics %26 Development, 13(4), 393–400. https://doi.org/10.1016/s0959-437x(03)00085-6
Vukicevic,, S., Kleinman,, H. K., Luyten,, F. P., Roberts,, A. B., Roche,, N. S., & Reddi,, A. H. (1992). Identification of multiple active growth factors in basement membrane Matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Experimental Cell Research, 202(1), 1–8. https://doi.org/10.1016/0014-4827(92)90397-q
Watson,, C. L., Mahe,, M. M., Munera,, J., Howell,, J. C., Sundaram,, N., Poling,, H. M., … Helmrath,, M. A. (2014). An in vivo model of human small intestine using pluripotent stem cells. Nature Medicine, 20(11), 1310–1314. https://doi.org/10.1038/nm.3737
Weaver,, M., Dunn,, N. R., & Hogan,, B. L. (2000). Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development, 127(12), 2695–2704 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10821767
Whitcutt,, M. J., Adler,, K. B., & Wu,, R. (1988). A biphasic chamber system for maintaining polarity of differentiation of cultured respiratory tract epithelial cells. In Vitro Cellular %26 Developmental Biology, 24(5), 420–428. https://doi.org/10.1007/BF02628493
Whitman,, M. (2001). Nodal signaling in early vertebrate embryos: Themes and variations. Developmental Cell, 1(5), 605–617 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11709181
Wong,, A. P., Bear,, C. E., Chin,, S., Pasceri,, P., Thompson,, T. O., Huan,, L. J., … Rossant,, J. (2012). Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nature Biotechnology, 30(9), 876–882. https://doi.org/10.1038/nbt.2328
Workman,, M. J., Mahe,, M. M., Trisno,, S., Poling,, H. M., Watson,, C. L., Sundaram,, N., … Wells,, J. M. (2017). Engineered human pluripotent‐stem‐cell‐derived intestinal tissues with a functional enteric nervous system. Nature Medicine, 23(1), 49–59. https://doi.org/10.1038/nm.4233
Xia,, Y., Nivet,, E., Sancho‐Martinez,, I., Gallegos,, T., Suzuki,, K., Okamura,, D., … Izpisua Belmonte,, J. C. (2013). Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor‐like cells. Nature Cell Biology, 15(12), 1507–1515. https://doi.org/10.1038/ncb2872
Xu,, H., Jiao,, Y., Qin,, S., Zhao,, W., Chu,, Q., & Wu,, K. (2018). Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine. Experimental Hematology %26 Oncology, 7, 30. https://doi.org/10.1186/s40164-018-0122-9
Yamamoto,, Y., Gotoh,, S., Korogi,, Y., Seki,, M., Konishi,, S., Ikeo,, S., … Mishima,, M. (2017). Long‐term expansion of alveolar stem cells derived from human iPS cells in organoids. Nature Methods, 14(11), 1097–1106. https://doi.org/10.1038/nmeth.4448
Yamanaka,, S. (2009). A fresh look at iPS cells. Cell, 137(1), 13–17. https://doi.org/10.1016/j.cell.2009.03.034
Yu,, J., Vodyanik,, M. A., Smuga‐Otto,, K., Antosiewicz‐Bourget,, J., Frane,, J. L., Tian,, S., … Thomson,, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920. https://doi.org/10.1126/science.1151526
Yusen,, R. D., Christie,, J. D., Edwards,, L. B., Kucheryavaya,, A. Y., Benden,, C., Dipchand,, A. I., … Lung,, T. (2013). The registry of the International Society for Heart and Lung Transplantation: Thirtieth adult Lung and heart‐Lung transplant report—2013; focus theme: Age. The Journal of Heart and Lung Transplantation, 32(10), 965–978. https://doi.org/10.1016/j.healun.2013.08.007
Ziegler,, C. G. K., Allon,, S. J., Nyquist,, S. K., Mbano,, I. M., Miao,, V. N., Tzouanas,, C. N., … Network,, H. C. A. L. B. (2020). SARS‐CoV‐2 receptor ACE2 is an interferon‐stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell, 181, 1016–1035.e19. https://doi.org/10.1016/j.cell.2020.04.035

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