Organoids are complex multicellular three-dimensional (3D) in vitro models that are designed to allow accurate studies of the molecular processes and pathologies of human organs. Organoids can be derived from a variety of cell types, such as human primary progenitor cells, pluripotent stem cells, or tumor-derived cells and can be co-cultured with immune or microbial cells to further mimic the tissue niche. Here, we focus on the development of 3D lung organoids and their use as disease models and drug screening tools. We introduce the various experimental approaches used to model complex human diseases and analyze their advantages and disadvantages. We also discuss validation of the organoids and their physiological relevance to the study of lung diseases. Furthermore, we summarize the current use of lung organoids as models of host-pathogen interactions and human lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or SARS-CoV-2 infection. Moreover, we discuss the use of lung organoids derived from tumor cells as lung cancer models and their application in personalized cancer medicine research. Finally, we outline the future of research in the field of human induced pluripotent stem cell-derived organoids.

Department of Biology Faculty of Medicine Masaryk University Brno Czechia

Department of Cell Biology Faculty of Science Charles University Prague Czechia

Department of Medicine and Surgery University of Perugia Perugia Italy

Institute of Hematology and Blood Transfusion Prague Czechia

International Clinical Research Center St Anne's University Hospital Brno Brno Czechia

Zobrazit více v PubMed

Aichler M., Kunzke T., Buck A., Sun N., Ackermann M., Jonigk D., et al. (2018). Molecular Similarities and Differences from Human Pulmonary Fibrosis and Corresponding Mouse Model: MALDI Imaging Mass Spectrometry in Comparative Medicine. Lab. Invest. 98, 141–149. 10.1038/labinvest.2017.110 PubMed DOI

Angus D. C., van der Poll T. (2013). Severe Sepsis and Septic Shock. N. Engl. J. Med. 369, 840–851. 10.1056/nejmra1208623 PubMed DOI

Ardini-Poleske M. E., Clark R. F., Ansong C., Carson J. P., Corley R. A., Deutsch G. H., et al. (2017). LungMAP: The Molecular Atlas of Lung Development Program. Am. J. Physiology-Lung Cell. Mol. Physiology 313, L733–L740. 10.1152/ajplung.00139.2017 PubMed DOI PMC

Aziz M., Jacob A., Yang W. L., Matsuda A., Wang P. (2013). Current Trends in Inflammatory and Immunomodulatory Mediators in Sepsis. J. Leukoc. Biol. 93, 329–342. 10.1189/jlb.0912437 PubMed DOI PMC

Barcik W., Boutin R. C. T., Sokolowska M., Finlay B. B. (2020). The Role of Lung and Gut Microbiota in the Pathology of Asthma. Immunity 52, 241–255. 10.1016/j.immuni.2020.01.007 PubMed DOI PMC

Barkauskas C. E., Cronce M. J., Rackley C. R., Bowie E. J., Keene D. R., Stripp B. R., et al. (2013). Type 2 Alveolar Cells Are Stem Cells in Adult Lung. J. Clin. Invest. 123, 3025–3036. 10.1172/jci68782 PubMed DOI PMC

Barros A. S., Costa A., Sarmento B. (2021). Building Three-Dimensional Lung Models for Studying Pharmacokinetics of Inhaled Drugs. Adv. drug Deliv. Rev. 170, 386–395. 10.1016/j.addr.2020.09.008 PubMed DOI

Beigel J. H., Tomashek K. M., Dodd L. E., Mehta A. K., Zingman B. S., Kalil A. C., et al. (2020). Remdesivir for the Treatment of Covid-19 - Final Report. N. Engl. J. Med. 383, 1813–1826. 10.1056/nejmoa2007764 PubMed DOI PMC

Benam K. H., Villenave R., Lucchesi C., Varone A., Hubeau C., Lee H. H., et al. (2016). Small Airway-On-A-Chip Enables Analysis of Human Lung Inflammation and Drug Responses In Vitro . Nat. Methods 13, 151–157. 10.1038/nmeth.3697 PubMed DOI

Berkers G., van Mourik P., Vonk A. M., Kruisselbrink E., Dekkers J. F., de Winter-de Groot K. M., et al. (2019). Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis. Cell Rep. 26, 1701–1708. e3. 10.1016/j.celrep.2019.01.068 PubMed DOI

Bleijs M., van de Wetering M., Clevers H., Drost J. (2019). Xenograft and Organoid Model Systems in Cancer Research. EMBO J. 38, e101654. 10.15252/embj.2019101654 PubMed DOI PMC

Boyle M. A., Sequeira D. J., McNeill E. P., Criss Z. K., 2nd, Shroyer N. F., Speer A. L. (2021). Vivo Transplantation of Human Intestinal Organoids Enhances Select Tight Junction Gene Expression. J. Surg. Res. 259, 500–508. 10.1016/j.jss.2020.10.002 PubMed DOI PMC

Busslinger G. A., Weusten B. L. A., Bogte A., Begthel H., Brosens L. A. A., Clevers H. (2021). Human Gastrointestinal Epithelia of the Esophagus, Stomach, and Duodenum Resolved at Single-Cell Resolution. Cell Rep. 34, 108819. 10.1016/j.celrep.2021.108819 PubMed DOI

Castellani S., Di Gioia S., di Toma L., Conese M. (2018). Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis. Anal. Cell Pathol. (Amst) 2018, 3839803. 10.1155/2018/3839803 PubMed DOI PMC

Chanda D., Otoupalova E., Smith S. R., Volckaert T., De Langhe S. P., Thannickal V. J. (2019). Developmental Pathways in the Pathogenesis of Lung Fibrosis. Mol. Aspects Med. 65, 56–69. 10.1016/j.mam.2018.08.004 PubMed DOI PMC

Chang D., Sharma L. (2020). Harnessing Murine Microbiome Models to Study Human Lung Microbiome. Chest 157, 776–778. 10.1016/j.chest.2019.12.011 PubMed DOI PMC

Charavaryamath C., Janardhan K. S., Caldwell S., Singh B. (2006). Pulmonary Intravascular Monocytes/macrophages in a Rat Model of Sepsis. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 288, 1259–1271. 10.1002/ar.a.20401 PubMed DOI

Chen Y. W., Huang S. X., de Carvalho A., Ho S. H., Islam M. N., Volpi S., et al. (2017). A Three-Dimensional Model of Human Lung Development and Disease from Pluripotent Stem Cells. Nat. Cell Biol. 19, 542–549. 10.1038/ncb3510 PubMed DOI PMC

Choi J., Iich E., Lee J. H. (2016). Organogenesis of Adult Lung in a Dish: Differentiation, Disease and Therapy. Dev. Biol. 420, 278–286. 10.1016/j.ydbio.2016.10.002 PubMed DOI

Choi J., Park J. E., Tsagkogeorga G., Yanagita M., Koo B. K., Han N., et al. (2020). Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell Stem Cell 27, 366–382 e7. 10.1016/j.stem.2020.06.020 PubMed DOI PMC

Ciancanelli M. J., Huang S. X., Luthra P., Garner H., Itan Y., Volpi S., et al. (2015). Infectious Disease. Life-Threatening Influenza and Impaired Interferon Amplification in Human IRF7 Deficiency. Science 348, 448–453. 10.1126/science.aaa1578 PubMed DOI PMC

Clarke L. L., Grubb B. R., Gabriel S. E., Smithies O., Koller B. H., Boucher R. C. (1992). Defective Epithelial Chloride Transport in a Gene-Targeted Mouse Model of Cystic Fibrosis. Science 257, 1125–1128. 10.1126/science.257.5073.1125 PubMed DOI

Cleary S. J., Pitchford S. C., Amison R. T., Carrington R., Robaina Cabrera C. L., Magnen M., et al. (2020). Animal Models of Mechanisms of SARS-CoV-2 Infection and COVID-19 Pathology. Br. J. Pharmacol. 177, 4851–4865. 10.1111/bph.15143 PubMed DOI PMC

Clevers H. (2016). Modeling Development and Disease with Organoids. Cell 165, 1586–1597. 10.1016/j.cell.2016.05.082 PubMed DOI

Cortez A. R., Poling H. M., Brown N. E., Singh A., Mahe M. M., Helmrath M. A. (2018). Transplantation of Human Intestinal Organoids into the Mouse Mesentery: A More Physiologic and Anatomic Engraftment Site. Surgery 164, 643–650. 10.1016/j.surg.2018.04.048 PubMed DOI PMC

Croxtall J. D., Perry C. M. (2010). Lopinavir/Ritonavir: a Review of its Use in the Management of HIV-1 Infection. Drugs 70, 1885–1915. 10.2165/11204950-000000000-00000 PubMed DOI

Cunniff B., Druso J. E., van der Velden J. L. (2021). Lung Organoids: Advances in Generation and 3D-Visualization. Histochem Cell Biol. 155, 301–308. 10.1007/s00418-020-01955-w PubMed DOI PMC

Danahay H., Pessotti A. D., Coote J., Montgomery B. E., Xia D., Wilson A., et al. (2015). Notch2 Is Required for Inflammatory Cytokine-Driven Goblet Cell Metaplasia in the Lung. Cell Rep. 10, 239–252. 10.1016/j.celrep.2014.12.017 PubMed DOI

David B., Bafadhel M., Koenderman L., De Soyza A. (2021). Eosinophilic Inflammation in COPD: from an Inflammatory Marker to a Treatable Trait. Thorax 76, 188–195. 10.1136/thoraxjnl-2020-215167 PubMed DOI PMC

Davies H., Bignell G. R., Cox C., Stephens P., Edkins S., Clegg S., et al. (2002). Mutations of the BRAF Gene in Human Cancer. Nature 417, 949–954. 10.1038/nature00766 PubMed DOI

De Boeck K. (2020). Cystic Fibrosis in the Year 2020: A Disease with a New Face. Acta Paediatr. 109, 893–899. 10.1111/apa.15155 PubMed DOI

De Luca A., Pariano M., Cellini B., Costantini C., Villella V. R., Jose S. S., et al. (2017). The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways. Cell Rep. 20, 1667–1680. 10.1016/j.celrep.2017.07.063 PubMed DOI

Dekkers J. F., Wiegerinck C. L., de Jonge H. R., Bronsveld I., Janssens H. M., de Winter-de Groot K. M., et al. (2013). A Functional CFTR Assay Using Primary Cystic Fibrosis Intestinal Organoids. Nat. Med. 19, 939–945. 10.1038/nm.3201 PubMed DOI

Del Piccolo N., Shirure V. S., Bi Y., Goedegebuure S. P., Gholami S., Hughes C. C. W., et al. (2021). Tumor-on-chip Modeling of Organ-specific Cancer and Metastasis. Adv. drug Deliv. Rev. 175, 113798. 10.1016/j.addr.2021.05.008 PubMed DOI

Dong X., Xu S. B., Chen X., Tao M., Tang X. Y., Fang K. H., et al. (2021). Human Cerebral Organoids Establish Subcortical Projections in the Mouse Brain after Transplantation. Mol. psychiatry 26, 2964–2976. 10.1038/s41380-020-00910-4 PubMed DOI PMC

Drost J., Clevers H. (2018). Organoids in Cancer Research. Nat. Rev. Cancer 18, 407–418. 10.1038/s41568-018-0007-6 PubMed DOI

Duval K., Grover H., Han L.-H., Mou Y., Pegoraro A. F., Fredberg J., et al. (2017). Modeling Physiological Events in 2D vs. 3D Cell Culture. Physiology 32, 266–277. 10.1152/physiol.00036.2016 PubMed DOI PMC

Dwyer-Lindgren L., Bertozzi-Villa A., Stubbs R. W., Morozoff C., Shirude S., Naghavi M., et al. (2017). Trends and Patterns of Differences in Chronic Respiratory Disease Mortality Among US Counties, 1980-2014. Jama 318, 1136–1149. 10.1001/jama.2017.11747 PubMed DOI PMC

Dye B. R., Dedhia P. H., Miller A. J., Nagy M. S., White E. S., Shea L. D., et al. (2016). A Bioengineered Niche Promotes In Vivo Engraftment and Maturation of Pluripotent Stem Cell Derived Human Lung Organoids. Elife 5. 10.7554/eLife.19732 PubMed DOI PMC

Dye B. R., Hill D. R., Ferguson M. A., Tsai Y. H., Nagy M. S., Dyal R., et al. (2015). In Vitro generation of Human Pluripotent Stem Cell Derived Lung Organoids. Elife 4. 10.7554/eLife.05098 PubMed DOI PMC

Ebisudani T., Sugimoto S., Haga K., Mitsuishi A., Takai-Todaka R., Fujii M., et al. (2021). Direct Derivation of Human Alveolospheres for SARS-CoV-2 Infection Modeling and Drug Screening. Cell Rep. 35, 109218. 10.1016/j.celrep.2021.109218 PubMed DOI PMC

Engelman J. A., Zejnullahu K., Mitsudomi T., Song Y., Hyland C., Park J. O., et al. (2007). MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. Science 316, 1039–1043. 10.1126/science.1141478 PubMed DOI

Fajgenbaum D. C., June C. H. (2020). Cytokine Storm. N. Engl. J. Med. 383, 2255–2273. 10.1056/nejmra2026131 PubMed DOI PMC

Fiorini E., Veghini L., Corbo V. (2020). Modeling Cell Communication in Cancer with Organoids: Making the Complex Simple. Front. Cell Dev. Biol. 8, 166. 10.3389/fcell.2020.00166 PubMed DOI PMC

Firth A. L., Menon T., Parker G. S., Qualls S. J., Lewis B. M., Ke E., et al. (2015). Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs. Cell Rep. 12, 1385–1390. 10.1016/j.celrep.2015.07.062 PubMed DOI PMC

Franks T. J., Colby T. V., Travis W. D., Tuder R. M., Reynolds H. Y., Brody A. R., et al. (2008). Resident Cellular Components of the Human Lung: Current Knowledge and Goals for Research on Cell Phenotyping and Function. Proc. Am. Thorac. Soc. 5, 763–766. 10.1513/pats.200803-025hr PubMed DOI

Gazdar A. F., Girard L., Lockwood W. W., Lam W. L., Minna J. D. (2010). Lung Cancer Cell Lines as Tools for Biomedical Discovery and Research. J. Natl. Cancer Inst. 102, 1310–1321. 10.1093/jnci/djq279 PubMed DOI PMC

Gilpin S. E., Ren X., Okamoto T., Guyette J. P., Mou H., Rajagopal J., et al. (2014). Enhanced Lung Epithelial Specification of Human Induced Pluripotent Stem Cells on Decellularized Lung Matrix. Ann. Thorac. Surg. 98, 1721–1729. 10.1016/j.athoracsur.2014.05.080 PubMed DOI PMC

Gkatzis K., Taghizadeh S., Huh D., Stainier D. Y. R., Bellusci S. (2018). Use of Three-Dimensional Organoids and Lung-On-A-Chip Methods to Study Lung Development, Regeneration and Disease. Eur. Respir. J. 52. 10.1183/13993003.00876-2018 PubMed DOI

Gottschling S., Jauch A., Kuner R., Herpel E., Mueller-Decker K., Schnabel P. A., et al. (2012). Establishment and Comparative Characterization of Novel Squamous Cell Non-small Cell Lung Cancer Cell Lines and Their Corresponding Tumor Tissue. Lung cancer 75, 45–57. 10.1016/j.lungcan.2011.05.020 PubMed DOI

Grein J., Ohmagari N., Shin D., Diaz G., Asperges E., Castagna A., et al. (2020). Compassionate Use of Remdesivir for Patients with Severe Covid-19. N. Engl. J. Med. 382, 2327–2336. 10.1056/nejmoa2007016 PubMed DOI PMC

Grubb B. R., Boucher R. C. (1999). Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, S193–S214. 10.1152/physrev.1999.79.1.s193 PubMed DOI

Guilbault C., Saeed Z., Downey G. P., Radzioch D. (2007). Cystic Fibrosis Mouse Models. Am. J. Respir. Cell Mol. Biol. 36, 1–7. 10.1165/rcmb.2006-0184tr PubMed DOI

Gunti S., Hoke A. T. K., Vu K. P., London N. R., Jr. (2021). Organoid and Spheroid Tumor Models: Techniques and Applications. Cancers 13. 10.3390/cancers13040874 PubMed DOI PMC

Habiel D. M., Espindola M. S., Coelho A. L., Hogaboam C. M. (2018). Modeling Idiopathic Pulmonary Fibrosis in Humanized Severe Combined Immunodeficient Mice. Am. J. Pathology 188, 891–903. 10.1016/j.ajpath.2017.12.020 PubMed DOI PMC

Hai J., Zhang H., Zhou J., Wu Z., Chen T., Papadopoulos E., et al. (2020). Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy. Clin. Cancer Res. 26, 3431–3442. 10.1158/1078-0432.ccr-19-1627 PubMed DOI PMC

Hawkins F. J., Suzuki S., Beermann M. L., Barilla C., Wang R., Villacorta-Martin C., et al. (2021). Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells. Cell stem Cell 28, 79–95 e8. 10.1016/j.stem.2020.09.017 PubMed DOI PMC

Hegab A. E., Arai D., Gao J., Kuroda A., Yasuda H., Ishii M., et al. (2015). Mimicking the Niche of Lung Epithelial Stem Cells and Characterization of Several Effectors of Their In Vitro Behavior. Stem Cell Res. 15, 109–121. 10.1016/j.scr.2015.05.005 PubMed DOI

Hortova-Kohoutkova M., De Zuani M., Laznickova P., Bendickova K., Mrkva O., Andrejcinova I., et al. (2021). Polymorphonuclear Cells Show Features of Dysfunctional Activation during Fatal Sepsis. Front. Immunol. 12, 741484. 10.3389/fimmu.2021.741484 PubMed DOI PMC

Hortova-Kohoutkova M., Tidu F., De Zuani M., Sramek V., Helan M., Fric J. (2020). Phagocytosis-Inflammation Crosstalk in Sepsis: New Avenues for Therapeutic Intervention. Shock 54, 606–614. 10.1097/shk.0000000000001541 PubMed DOI PMC

Hu Y., Sui X., Song F., Li Y., Li K., Chen Z., et al. (2021). Lung Cancer Organoids Analyzed on Microwell Arrays Predict Drug Responses of Patients within a Week. Nat. Commun. 12, 2581. 10.1038/s41467-021-22676-1 PubMed DOI PMC

Huang H., Feng H., Zhuge D. (2019). M1 Macrophage Activated by Notch Signal Pathway Contributed to Ventilator-Induced Lung Injury in Chronic Obstructive Pulmonary Disease Model. J. Surg. Res. 244, 358–367. 10.1016/j.jss.2019.06.060 PubMed DOI

Huang Y., Huang Z., Tang Z., Chen Y., Huang M., Liu H., et al. (2021). Research Progress, Challenges, and Breakthroughs of Organoids as Disease Models. Front. Cell Dev. Biol. 9, 740574. 10.3389/fcell.2021.740574 PubMed DOI PMC

Huh D., Leslie D. C., Matthews B. D., Fraser J. P., Jurek S., Hamilton G. A., et al. (2012). A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-On-A-Chip Microdevice. Sci. Transl. Med. 4, 159ra147. 10.1126/scitranslmed.3004249 PubMed DOI PMC

Ibricevic A., Pekosz A., Walter M. J., Newby C., Battaile J. T., Brown E. G., et al. (2006). Influenza Virus Receptor Specificity and Cell Tropism in Mouse and Human Airway Epithelial Cells. J. virology 80, 7469–7480. 10.1128/jvi.02677-05 PubMed DOI PMC

Jacob A., Morley M., Hawkins F., McCauley K. B., Jean J. C., Heins H., et al. (2017). Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell stem Cell 21, 472–488 e10. 10.1016/j.stem.2017.08.014 PubMed DOI PMC

Jose S. S., De Zuani M., Tidu F., Hortová Kohoutková M., Pazzagli L., Forte G., et al. (2020). Comparison of Two Human Organoid Models of Lung and Intestinal Inflammation Reveals Toll-like Receptor Signalling Activation and Monocyte Recruitment. Clin. Transl. Immunol. 9, e1131. 10.1002/cti2.1131 PubMed DOI PMC

Jung D. J., Shin T. H., Kim M., Sung C. O., Jang S. J., Jeong G. S. (2019). A One-Stop Microfluidic-Based Lung Cancer Organoid Culture Platform for Testing Drug Sensitivity. Lab a chip 19, 2854–2865. 10.1039/c9lc00496c PubMed DOI

Kapicibasi H. O., Kiraz H. A., Demir E. T., Adali Y., Elmas S. (2020). Pulmonary Effects of Ozone Therapy at Different Doses Combined with Antibioticotherapy in Experimental Sepsis Model. Acta Cir. Bras. 35, e202000604. 10.1590/s0102-865020200060000004 PubMed DOI PMC

Karelehto E., Cristella C., Yu X., Sridhar A., Hulsdouw R., de Haan K., et al. (2018). Polarized Entry of Human Parechoviruses in the Airway Epithelium. Front. Cell. Infect. Microbiol. 8, 294. 10.3389/fcimb.2018.00294 PubMed DOI PMC

Karzai W., Cui X., Mehlhorn B., Straube E., Hartung T., Gerstenberger E., et al. (2003). Protection with Antibody to Tumor Necrosis Factor Differs with Similarly Lethal Escherichia coli versus Staphylococcus aureus Pneumonia in Rats. Anesthesiology 99, 81–89. 10.1097/00000542-200307000-00016 PubMed DOI

Katsura H., Kobayashi Y., Tata P. R., Hogan B. L. M. (2019). IL-1 and TNFalpha Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration. Stem Cell Rep. 12, 657–666. 10.1016/j.stemcr.2019.02.013 PubMed DOI PMC

Katsura H., Sontake V., Tata A., Kobayashi Y., Edwards C. E., Heaton B. E., et al. (2020). Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction. Cell Stem Cell 27, 890–904. e8. 10.1016/j.stem.2020.10.005 PubMed DOI PMC

Kim J. H., An G. H., Kim J. Y., Rasaei R., Kim W. J., Jin X., et al. (2021). Human Pluripotent Stem-Cell-Derived Alveolar Organoids for Modeling Pulmonary Fibrosis and Drug Testing. Cell Death Discov. 7, 48. 10.1038/s41420-021-00439-7 PubMed DOI PMC

Kim J., Koo B. K., Knoblich J. A. (2020). Human Organoids: Model Systems for Human Biology and Medicine. Nat. Rev. Mol. Cell Biol. 21, 571–584. 10.1038/s41580-020-0259-3 PubMed DOI PMC

Kim M., Mun H., Sung C. O., Cho E. J., Jeon H. J., Chun S. M., et al. (2019). Patient-derived Lung Cancer Organoids as In Vitro Cancer Models for Therapeutic Screening. Nat. Commun. 10, 3991. 10.1038/s41467-019-11867-6 PubMed DOI PMC

King T. E., Jr., Bradford W. Z., Castro-Bernardini S., Fagan E. A., Glaspole I., Glassberg M. K., et al. (2014). A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. N. Engl. J. Med. 370, 2083–2092. 10.1056/nejmoa1402582 PubMed DOI

Kondo J., Inoue M. (2019). Application of Cancer Organoid Model for Drug Screening and Personalized Therapy. Cells 8. 10.3390/cells8050470 PubMed DOI PMC

Kumar A., Singh R., Kaur J., Pandey S., Sharma V., Thakur L., et al. (2021). Wuhan to World: The COVID-19 Pandemic. Front. Cell. Infect. Microbiol. 11, 596201. 10.3389/fcimb.2021.596201 PubMed DOI PMC

Kwak E. L., Sordella R., Bell D. W., Godin-Heymann N., Okimoto R. A., Brannigan B. W., et al. (2005). Irreversible Inhibitors of the EGF Receptor May Circumvent Acquired Resistance to Gefitinib. Proc. Natl. Acad. Sci. U.S.A. 102, 7665–7670. 10.1073/pnas.0502860102 PubMed DOI PMC

Lai Y., Wei X., Lin S., Qin L., Cheng L., Li P. (2017). Current Status and Perspectives of Patient-Derived Xenograft Models in Cancer Research. J. Hematol. Oncol. 10, 106. 10.1186/s13045-017-0470-7 PubMed DOI PMC

Lamb Y. N. (2020). Remdesivir: First Approval. Drugs 80, 1355–1363. 10.1007/s40265-020-01378-w PubMed DOI PMC

Lambrecht B. N., Hammad H., Fahy J. V. (2019). The Cytokines of Asthma. Immunity 50, 975–991. 10.1016/j.immuni.2019.03.018 PubMed DOI

Lamers M. M., van der Vaart J., Knoops K., Riesebosch S., Breugem T. I., Mykytyn A. Z., et al. (2021). An Organoid-Derived Bronchioalveolar Model for SARS-CoV-2 Infection of Human Alveolar Type II-like Cells. EMBO J. 40, e105912. 10.15252/embj.2020105912 PubMed DOI PMC

Lancaster M. A., Huch M. (2019). Disease Modelling in Human Organoids. Dis. Model Mech. 12. 10.1242/dmm.039347 PubMed DOI PMC

Lechner A. J., Driver I. H., Lee J., Conroy C. M., Nagle A., Locksley R. M., et al. (2017). Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration Following Pneumonectomy. Cell stem Cell 21, 120–134 e7. 10.1016/j.stem.2017.03.024 PubMed DOI PMC

Leeman K. T., Pessina P., Lee J. H., Kim C. F. (2019). Mesenchymal Stem Cells Increase Alveolar Differentiation in Lung Progenitor Organoid Cultures. Sci. Rep. 9, 6479. 10.1038/s41598-019-42819-1 PubMed DOI PMC

Leibel S. L., Winquist A., Tseu I., Wang J., Luo D., Shojaie S., et al. (2019). Reversal of Surfactant Protein B Deficiency in Patient Specific Human Induced Pluripotent Stem Cell Derived Lung Organoids by Gene Therapy. Sci. Rep. 9, 13450. 10.1038/s41598-019-49696-8 PubMed DOI PMC

Li Z., Qian Y., Li W., Liu L., Yu L., Liu X., et al. (2020). Human Lung Adenocarcinoma-Derived Organoid Models for Drug Screening. iScience 23, 101411. 10.1016/j.isci.2020.101411 PubMed DOI PMC

Mas C., Boda B., Caul Futy M., Huang S., Wisniewski L., Constant S. (2016). Establishment of a Tumour-Stroma Airway Model (OncoCilAir) to Accelerate the Development of Human Therapies against Lung Cancer. Altern. Lab. Anim. 44, 479–485. 10.1177/026119291604400509 PubMed DOI

Matute-Bello G., Frevert C. W., Martin T. R. (2008). Animal Models of Acute Lung Injury. Am. J. Physiology-Lung Cell. Mol. Physiology 295, L379–L399. 10.1152/ajplung.00010.2008 PubMed DOI PMC

Mehta P., Rahman Z., Ten Dijke P., Boukany P. E. (2022). Microfluidics Meets 3D Cancer Cell Migration. Trends Cancer S2405-8033 (22), 00072–00073. 10.1016/j.trecan.2022.03.006 PubMed DOI

Mifflin L., Ofengeim D., Yuan J. (2020). Receptor-interacting Protein Kinase 1 (RIPK1) as a Therapeutic Target. Nat. Rev. Drug Discov. 19, 553–571. 10.1038/s41573-020-0071-y PubMed DOI PMC

Min S., Kim S., Cho S. W. (2020). Gastrointestinal Tract Modeling Using Organoids Engineered with Cellular and Microbiota Niches. Exp. Mol. Med. 52, 227–237. 10.1038/s12276-020-0386-0 PubMed DOI PMC

Minasyan H. (2019). Sepsis: Mechanisms of Bacterial Injury to the Patient. Scand. J. Trauma Resusc. Emerg. Med. 27, 19. 10.1186/s13049-019-0596-4 PubMed DOI PMC

Minoo P., Hamdan H., Bu D., Warburton D., Stepanik P., deLemos R. (1995). TTF-1 Regulates Lung Epithelial Morphogenesis. Dev. Biol. 172, 694–698. 10.1006/dbio.1995.8080 PubMed DOI

Moeller A., Ask K., Warburton D., Gauldie J., Kolb M. (2008). The Bleomycin Animal Model: a Useful Tool to Investigate Treatment Options for Idiopathic Pulmonary Fibrosis? Int. J. Biochem. Cell Biol. 40, 362–382. 10.1016/j.biocel.2007.08.011 PubMed DOI PMC

Motomura T., Ueda K., Ohtani S., Hansen E., Ji L., Ito K., et al. (2010). Evaluation of Systemic External Microwave Hyperthermia for Treatment of Pleural Metastasis in Orthotopic Lung Cancer Model. Oncol. Rep. 24, 591–598. 10.3892/or_00000896 PubMed DOI

Mou H., Zhao R., Sherwood R., Ahfeldt T., Lapey A., Wain J., et al. (2012). Generation of Multipotent Lung and Airway Progenitors from Mouse ESCs and Patient-specific Cystic Fibrosis iPSCs. Cell stem Cell 10, 385–397. 10.1016/j.stem.2012.01.018 PubMed DOI PMC

Nandi M., Jackson S. K., Macrae D., Shankar-Hari M., Tremoleda J. L., Lilley E. (2020). Rethinking Animal Models of Sepsis - Working towards Improved Clinical Translation whilst Integrating the 3Rs. Clin. Sci. 134, 1715–1734. 10.1042/cs20200679 PubMed DOI PMC

Neal J. T., Kuo C. J. (2016). Organoids as Models for Neoplastic Transformation. Annu. Rev. Pathol. 11, 199–220. 10.1146/annurev-pathol-012615-044249 PubMed DOI

Ng-Blichfeldt J. P., Schrik A., Kortekaas R. K., Noordhoek J. A., Heijink I. H., Hiemstra P. S., et al. (2018). Retinoic Acid Signaling Balances Adult Distal Lung Epithelial Progenitor Cell Growth and Differentiation. EBioMedicine 36, 461–474. 10.1016/j.ebiom.2018.09.002 PubMed DOI PMC

Nikolic M. Z., Rawlins E. L. (2017). Lung Organoids and Their Use to Study Cell-Cell Interaction. Curr. Pathobiol. Rep. 5, 223–231. PubMed PMC

Nossa R., Costa J., Cacopardo L., Ahluwalia A. (2021). Breathing In Vitro: Designs and Applications of Engineered Lung Models. J. Tissue Eng. 12, 20417314211008696. 10.1177/20417314211008696 PubMed DOI PMC

Pan H., Deutsch G. H., Deutsch G. H., Wert S. E., Consortium N. M. A. o. L. D. P. (2019). Comprehensive Anatomic Ontologies for Lung Development: A Comparison of Alveolar Formation and Maturation within Mouse and Human Lung. J. Biomed. Semant. 10, 18. 10.1186/s13326-019-0209-1 PubMed DOI PMC

Pao W., Miller V. A., Politi K. A., Riely G. J., Somwar R., Zakowski M. F., et al. (2005). Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Med. 2, e73. 10.1371/journal.pmed.0020073 PubMed DOI PMC

Paolicelli G., Luca A. D., Jose S. S., Antonini M., Teloni I., Fric J., et al. (2019). Using Lung Organoids to Investigate Epithelial Barrier Complexity and IL-17 Signaling during Respiratory Infection. Front. Immunol. 10, 323. 10.3389/fimmu.2019.00323 PubMed DOI PMC

Park I., Kim M., Choe K., Song E., Seo H., Hwang Y., et al. (2019). Neutrophils Disturb Pulmonary Microcirculation in Sepsis-Induced Acute Lung Injury. Eur. Respir. J. 53. 10.1183/13993003.00786-2018 PubMed DOI PMC

Poling H. M., Wu D., Brown N., Baker M., Hausfeld T. A., Huynh N., et al. (2018). Mechanically Induced Development and Maturation of Human Intestinal Organoids In Vivo . Nat. Biomed. Eng. 2, 429–442. 10.1038/s41551-018-0243-9 PubMed DOI PMC

Pollard C. A., Morran M. P., Nestor-Kalinoski A. L. (2020). The COVID-19 Pandemic: a Global Health Crisis. Physiol. genomics 52, 549–557. 10.1152/physiolgenomics.00089.2020 PubMed DOI PMC

Porotto M., Ferren M., Chen Y. W., Siu Y., Makhsous N., Rima B., et al. (2019). Authentic Modeling of Human Respiratory Virus Infection in Human Pluripotent Stem Cell-Derived Lung Organoids. mBio 10. 10.1128/mBio.00723-19 PubMed DOI PMC

Pratilas C. A., Hanrahan A. J., Halilovic E., Persaud Y., Soh J., Chitale D., et al. (2008). Genetic Predictors of MEK Dependence in Non-small Cell Lung Cancer. Cancer Res. 68, 9375–9383. 10.1158/0008-5472.can-08-2223 PubMed DOI PMC

Quantius J., Schmoldt C., Vazquez-Armendariz A. I., Becker C., El Agha E., Wilhelm J., et al. (2016). Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair. PLoS Pathog. 12, e1005544. 10.1371/journal.ppat.1005544 PubMed DOI PMC

Rabata A., Fedr R., Soucek K., Hampl A., Koledova Z. (2020). 3D Cell Culture Models Demonstrate a Role for FGF and WNT Signaling in Regulation of Lung Epithelial Cell Fate and Morphogenesis. Front. Cell Dev. Biol. 8, 574. 10.3389/fcell.2020.00574 PubMed DOI PMC

Raghu G., Chen S.-Y., Yeh W.-S., Maroni B., Li Q., Lee Y.-C., et al. (2014). Idiopathic Pulmonary Fibrosis in US Medicare Beneficiaries Aged 65 Years and Older: Incidence, Prevalence, and Survival, 2001-11. Lancet Respir. Med. 2, 566–572. 10.1016/s2213-2600(14)70101-8 PubMed DOI

Ramachandran P., Matchett K. P., Dobie R., Wilson-Kanamori J. R., Henderson N. C. (2020). Single-cell Technologies in Hepatology: New Insights into Liver Biology and Disease Pathogenesis. Nat. Rev. Gastroenterol. Hepatol. 17, 457–472. 10.1038/s41575-020-0304-x PubMed DOI

Ramamoorthy P., Thomas S. M., Kaushik G., Subramaniam D., Chastain K. M., Dhar A., et al. (2019). Metastatic Tumor-In-A-Dish, a Novel Multicellular Organoid to Study Lung Colonization and Predict Therapeutic Response. Cancer Res. 79, 1681–1695. 10.1158/0008-5472.can-18-2602 PubMed DOI PMC

Reyes M., Filbin M. R., Bhattacharyya R. P., Billman K., Eisenhaure T., Hung D. T., et al. (2020). An Immune-Cell Signature of Bacterial Sepsis. Nat. Med. 26, 333–340. 10.1038/s41591-020-0752-4 PubMed DOI PMC

Richeldi L., du Bois R. M., Raghu G., Azuma A., Brown K. K., Costabel U., et al. (2014). Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. N. Engl. J. Med. 370, 2071–2082. 10.1056/nejmoa1402584 PubMed DOI

Riemondy K. A., Jansing N. L., Jiang P., Redente E. F., Gillen A. E., Fu R., et al. (2019). Single Cell RNA Sequencing Identifies TGFbeta as a Key Regenerative Cue Following LPS-Induced Lung Injury. JCI Insight 5. 10.1172/jci.insight.123637 PubMed DOI PMC

Rudd K. E., Johnson S. C., Agesa K. M., Shackelford K. A., Tsoi D., Kievlan D. R., et al. (2020). Global, Regional, and National Sepsis Incidence and Mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 395, 200–211. 10.1016/s0140-6736(19)32989-7 PubMed DOI PMC

Sachs N., Papaspyropoulos A., Zomer-van Ommen D. D., Heo I., Bottinger L., Klay D., et al. (2019). Long-term Expanding Human Airway Organoids for Disease Modeling. EMBO J. 38. 10.15252/embj.2018100300 PubMed DOI PMC

Salahudeen A. A., Choi S. S., Rustagi A., Zhu J., van Unen V., de la O. S., et al. (2020). Progenitor Identification and SARS-CoV-2 Infection in Human Distal Lung Organoids. Nature 588, 670–675. 10.1038/s41586-020-3014-1 PubMed DOI PMC

Sato T., Morita M., Tanaka R., Inoue Y., Nomura M., Sakamoto Y., et al. (2017). Ex Vivo model of Non-small Cell Lung Cancer Using Mouse Lung Epithelial Cells. Oncol. Lett. 14, 6863–6868. 10.3892/ol.2017.7098 PubMed DOI PMC

Sato T., Vries R. G., Snippert H. J., van de Wetering M., Barker N., Stange D. E., et al. (2009). Single Lgr5 Stem Cells Build Crypt-Villus Structures In Vitro without a Mesenchymal Niche. Nature 459, 262–265. 10.1038/nature07935 PubMed DOI

Schittny J. C. (2017). Development of the Lung. Cell Tissue Res. 367, 427–444. 10.1007/s00441-016-2545-0 PubMed DOI PMC

Schutgens F., Clevers H. (2020). Human Organoids: Tools for Understanding Biology and Treating Diseases. Annu. Rev. Pathol. 15, 211–234. 10.1146/annurev-pathmechdis-012419-032611 PubMed DOI

Semaniakou A., Croll R. P., Chappe V. (2018). Animal Models in the Pathophysiology of Cystic Fibrosis. Front. Pharmacol. 9, 1475. 10.3389/fphar.2018.01475 PubMed DOI PMC

Seok J., Warren H. S., Cuenca A. G., Mindrinos M. N., Baker H. V., Xu W., et al. (2013). Host Response to Injury, Genomic Responses in Mouse Models Poorly Mimic Human Inflammatory Diseases. Proc. Natl. Acad. Sci. U. S. A. 110, 3507–3512. 10.1073/pnas.1222878110 PubMed DOI PMC

Sevransky J. E., Martin G. S., Shanholtz C., Mendez-Tellez P. A., Pronovost P., Brower R., et al. (2009). Mortality in Sepsis versus Non-sepsis Induced Acute Lung Injury. Crit. care 13, R150. 10.1186/cc8048 PubMed DOI PMC

Sharma A., Toepfer C. N., Ward T., Wasson L., Agarwal R., Conner D. A., et al. (2018). CRISPR/Cas9-Mediated Fluorescent Tagging of Endogenous Proteins in Human Pluripotent Stem Cells. Curr. Protoc. Hum. Genet. 96, 21 11 1–21 11 20. 10.1002/cphg.52 PubMed DOI PMC

Shen Y., Chen L., Wang M., Lin D., Liang Z., Song P., et al. (2017). Flagellar Hooks and Hook Protein FlgE Participate in Host Microbe Interactions at Immunological Level. Sci. Rep. 7, 1433. 10.1038/s41598-017-01619-1 PubMed DOI PMC

Shi R., Radulovich N., Ng C., Liu N., Notsuda H., Cabanero M., et al. (2020). Organoid Cultures as Preclinical Models of Non-small Cell Lung Cancer. Clin. Cancer Res. 26, 1162–1174. 10.1158/1078-0432.ccr-19-1376 PubMed DOI

Shmidt E. N., Nitkin A. Y. (2004). Pathology of Mouse Models of Human Lung Cancer. Comp. Med. 54, 23–26. PubMed

Singer M., Deutschman C. S., Seymour C. W., Shankar-Hari M., Annane D., Bauer M., et al. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810. 10.1001/jama.2016.0287 PubMed DOI PMC

Snouwaert J. N., Brigman K. K., Latour A. M., Malouf N. N., Boucher R. C., Smithies O., et al. (1992). An Animal Model for Cystic Fibrosis Made by Gene Targeting. Science 257, 1083–1088. 10.1126/science.257.5073.1083 PubMed DOI

Stahl O., Loffler B., Haier J., Mardin W. A., Mees S. T. (2013). Mimicry of Human Sepsis in a Rat Model-Pprospects and Limitations. J. Surg. Res. 179, e167–75. 10.1016/j.jss.2012.01.042 PubMed DOI

Strikoudis A., Cieslak A., Loffredo L., Chen Y. W., Patel N., Saqi A., et al. (2019). Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells. Cell Rep. 27, 3709–3723. e5. 10.1016/j.celrep.2019.05.077 PubMed DOI PMC

Sucre J. M., Wilkinson D., Vijayaraj P., Paul M., Dunn B., Alva-Ornelas J. A., et al. (2016). A Three-Dimensional Human Model of the Fibroblast Activation that Accompanies Bronchopulmonary Dysplasia Identifies Notch-Mediated Pathophysiology. Am. J. physiology. Lung Cell. Mol. physiology 310, L889–L898. 10.1152/ajplung.00446.2015 PubMed DOI PMC

Suezawa T., Kanagaki S., Moriguchi K., Masui A., Nakao K., Toyomoto M., et al. (2021). Disease Modeling of Pulmonary Fibrosis Using Human Pluripotent Stem Cell-Derived Alveolar Organoids. Stem Cell Rep. 16, 2973–2987. 10.1016/j.stemcr.2021.10.015 PubMed DOI PMC

Sweeney R. M., McAuley D. F. (2016). Acute Respiratory Distress Syndrome. Lancet 388, 2416–2430. 10.1016/s0140-6736(16)00578-x PubMed DOI PMC

Takahashi T., Nau M. M., Chiba I., Birrer M. J., Rosenberg R. K., Vinocour M., et al. (1989). p53: a Frequent Target for Genetic Abnormalities in Lung Cancer. Science 246, 491–494. 10.1126/science.2554494 PubMed DOI

Tamminga M., Hiltermann T. J. N., Schuuring E., Timens W., Fehrmann R. S., Groen H. J. (2020). Immune Microenvironment Composition in Non-small Cell Lung Cancer and its Association with Survival. Clin. Transl. Immunol. 9, e1142. 10.1002/cti2.1142 PubMed DOI PMC

Tan Q., Choi K. M., Sicard D., Tschumperlin D. J. (2017). Human Airway Organoid Engineering as a Step toward Lung Regeneration and Disease Modeling. Biomaterials 113, 118–132. 10.1016/j.biomaterials.2016.10.046 PubMed DOI PMC

Tanabe N., McDonough J. E., Vasilescu D. M., Ikezoe K., Verleden S. E., Xu F., et al. (2020). Pathology of Idiopathic Pulmonary Fibrosis Assessed by a Combination of Microcomputed Tomography, Histology, and Immunohistochemistry. Am. J. pathology 190, 2427–2435. 10.1016/j.ajpath.2020.09.001 PubMed DOI

Tashiro J., Rubio G. A., Limper A. H., Williams K., Elliot S. J., Ninou I., et al. (2017). Exploring Animal Models that Resemble Idiopathic Pulmonary Fibrosis. Front. Med. 4, 118. 10.3389/fmed.2017.00118 PubMed DOI PMC

Tian L., Gao J., Garcia I. M., Chen H. J., Castaldi A., Chen Y. W. (2021). Human Pluripotent Stem Cell-Derived Lung Organoids: Potential Applications in Development and Disease Modeling. Wiley Interdiscip. Rev. Dev. Biol. 10, e399. 10.1002/wdev.399 PubMed DOI

Tindle C., Fuller M., Fonseca A., Taheri S., Ibeawuchi S. R., Beutler N., et al. (2021). Adult Stem Cell-Derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19. Elife 10. 10.7554/eLife.66417 PubMed DOI PMC

van den Berg C. W., Ritsma L., Avramut M. C., Wiersma L. E., van den Berg B. M., Leuning D. G., et al. (2018). Renal Subcapsular Transplantation of PSC-Derived Kidney Organoids Induces Neo-Vasculogenesis and Significant Glomerular and Tubular Maturation In Vivo . Stem Cell Rep. 10, 751–765. 10.1016/j.stemcr.2018.01.041 PubMed DOI PMC

van der Sanden S. M. G., Sachs N., Koekkoek S. M., Koen G., Pajkrt D., Clevers H., et al. (2018). Enterovirus 71 Infection of Human Airway Organoids Reveals VP1-145 as a Viral Infectivity Determinant. Emerg. microbes Infect. 7, 84. 10.1038/s41426-018-0077-2 PubMed DOI PMC

van Geffen C., Deissler A., Quante M., Renz H., Hartl D., Kolahian S. (2021). Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes? Front. Immunol. 12, 663203. 10.3389/fimmu.2021.663203 PubMed DOI PMC

Varghese B., Ling Z., Ren X. (2022). Reconstructing the Pulmonary Niche with Stem Cells: a Lung Story. Stem Cell Res. Ther. 13, 161. 10.1186/s13287-022-02830-2 PubMed DOI PMC

Vlachogiannis G., Hedayat S., Vatsiou A., Jamin Y., Fernandez-Mateos J., Khan K., et al. (2018). Patient-derived Organoids Model Treatment Response of Metastatic Gastrointestinal Cancers. Science 359, 920–926. 10.1126/science.aao2774 PubMed DOI PMC

Walters D. M., Kleeberger S. R. (2008). Mouse Models of Bleomycin-Induced Pulmonary Fibrosis. Curr. Protoc. Pharmacol. Chapter 5, Unit 5.46. 10.1002/0471141755.ph0546s40 PubMed DOI

Wang H. M., Bodenstein M., Markstaller K. (2008). Overview of the Pathology of Three Widely Used Animal Models of Acute Lung Injury. Eur. Surg. Res. 40, 305–316. 10.1159/000121471 PubMed DOI

Wang J. E., Dahle M. K., Yndestad A., Bauer I., McDonald M. C., Aukrust P., et al. (2004). Peptidoglycan of Staphylococcus aureus Causes Inflammation and Organ Injury in the Rat. Crit. Care Med. 32, 546–552. 10.1097/01.ccm.0000109775.22138.8f PubMed DOI

Wang J., Li X., Chen H. (2020). Organoid Models in Lung Regeneration and Cancer. Cancer Lett. 475, 129–135. 10.1016/j.canlet.2020.01.030 PubMed DOI

Wang L., Liu H., Jiao Y., Wang E., Clark S., Postlethwaite A., et al. (2015). Differences between Mice and Humans in Regulation and the Molecular Network of Collagen, Type III, Alpha-1 at the Gene Expression Level: Obstacles that Translational Research Must Overcome. Int. J. Mol. Sci. 16, 15031–15056. 10.3390/ijms160715031 PubMed DOI PMC

Wang R., McCauley K. B., Kotton D. N., Hawkins F. (2020). Differentiation of Human Airway-Organoids from Induced Pluripotent Stem Cells (iPSCs). Methods Cell Biol. 159, 95–114. 10.1016/bs.mcb.2020.03.008 PubMed DOI

Wilkinson D. C., Alva-Ornelas J. A., Sucre J. M., Vijayaraj P., Durra A., Richardson W., et al. (2017). Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Stem cells Transl. Med. 6, 622–633. 10.5966/sctm.2016-0192 PubMed DOI PMC

Williams K., Roman J. (2016). Studying Human Respiratory Disease in Animals - Role of Induced and Naturally Occurring Models. J. Pathol. 238, 220–232. 10.1002/path.4658 PubMed DOI

Wong A. P., Bear C. E., Chin S., Pasceri P., Thompson T. O., Huan L. J., et al. (2012). Directed Differentiation of Human Pluripotent Stem Cells into Mature Airway Epithelia Expressing Functional CFTR Protein. Nat. Biotechnol. 30, 876–882. 10.1038/nbt.2328 PubMed DOI PMC

Xu G., Li Y., Zhang S., Peng H., Wang Y., Li D., et al. (2021). SARS-CoV-2 Promotes RIPK1 Activation to Facilitate Viral Propagation. Cell Res. 31, 1230–1243. 10.1038/s41422-021-00578-7 PubMed DOI PMC

Xu Z., Gao Y., Hao Y., Li E., Wang Y., Zhang J., et al. (2013). Application of a Microfluidic Chip-Based 3D Co-culture to Test Drug Sensitivity for Individualized Treatment of Lung Cancer. Biomaterials 34, 4109–4117. 10.1016/j.biomaterials.2013.02.045 PubMed DOI

Yoshida G. J. (2020). Applications of Patient-Derived Tumor Xenograft Models and Tumor Organoids. J. Hematol. Oncol. 13, 4. 10.1186/s13045-019-0829-z PubMed DOI PMC

Zhu F., Zuo L., Hu R., Wang J., Yang Z., Qi X., et al. (2021). Effect of Immune Cell Infiltration on Occurrence of Pulmonary Hypertension in Pulmonary Fibrosis Patients Based on Gene Expression Profiles. Front. Med. 8, 671617. 10.3389/fmed.2021.671617 PubMed DOI PMC

Zscheppang K., Berg J., Hedtrich S., Verheyen L., Wagner D. E., Suttorp N., et al. (2018). Human Pulmonary 3D Models for Translational Research. Biotechnol. J. 13. 10.1002/biot.201700341 PubMed DOI PMC

Serotonin attenuates tumor necrosis factor-induced intestinal inflammation by interacting with human mucosal tissue

Activation of TLRs by Opportunistic Fungi in Lung Organoids