Human airway organoid engineering as a step toward lung regeneration and disease modeling
Open accessAbstract
Organoids represent both a potentially powerful tool for the study cell-cell interactions within tissue-like environments, and a platform for tissue regenerative approaches. The development of lung tissue-like organoids from human adult-derived cells has not previously been reported. Here we combined human adult primary bronchial epithelial cells, lung fibroblasts, and lung microvascular endothelial cells in supportive 3D culture conditions to generate airway organoids. We demonstrate that randomly-seeded mixed cell populations undergo rapid condensation and self-organization into discrete epithelial and endothelial structures that are mechanically robust and stable during long term culture. After condensation airway organoids generate invasive multicellular tubular structures that recapitulate limited aspects of branching morphogenesis, and require actomyosin-mediated force generation and YAP/TAZ activation. Despite the proximal source of primary epithelium used in the airway organoids, discrete areas of both proximal and distal epithelial markers were observed over time in culture, demonstrating remarkable epithelial plasticity within the context of organoid cultures. Airway organoids also exhibited complex multicellular responses to a prototypical fibrogenic stimulus (TGF-β1) in culture, and limited capacity to undergo continued maturation and engraftment after ectopic implantation under the murine kidney capsule. These results demonstrate that the airway organoid system developed here represents a novel tool for the study of disease-relevant cell-cell interactions, and establishes this platform as a first step toward cell-based therapy for chronic lung diseases based on de novo engineering of implantable airway tissues.
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Spheroid cultures have enabled the engineering of heart, liver, and lung fibrosis models.
“For example, spheroid cultures have enabled the engineering of heart, liver, and lung fibrosis models6,15–18”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [18]
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Mammoto, T., & Mammoto, A. (2014) · Journal of Visualized Experiments · doi:10.3791/52012 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Long‐term expanding human airway organoids for disease modeling
Sachs, N., Papaspyropoulos, A., Zomer‐van Ommen, D. D., Heo, I., Böttinger, L., Klay, D., Weeber, F., Huelsz‐Prince, G., Iakobachvili, N., Amatngalim, G. D., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100300 · Cited by 1,082 · see citing works
Daly, A. C., Davidson, M. D., & Burdick, J. A. (2021) · Nature Communications · doi:10.1038/s41467-021-21029-2 · Cited by 470 · see citing works
Xenograft and organoid model systems in cancer research
Bleijs, M., van de Wetering, M., Clevers, H., & Drost, J. (2019) · The EMBO Journal · doi:10.15252/embj.2019101654 · Cited by 400 · see citing works
Matrix biomechanics and dynamics in pulmonary fibrosis
Haak, A. J., Tan, Q., & Tschumperlin, D. J. (2018) · Matrix Biology · doi:10.1016/j.matbio.2017.12.004 · Cited by 95 · see citing works
Self-citationAwatade, N. T., Wong, S. L., Hewson, C. K., Fawcett, L. K., Kicic, A., Jaffe, A., & Waters, S. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01429 · Cited by 92 · see citing works
Exploring single cells in space and time during tissue development, homeostasis and regeneration
Mayr, U., Serra, D., & Liberali, P. (2019) · Development · doi:10.1242/dev.176727 · Cited by 63 · see citing works
Endothelialized Bronchioalveolar Lung Organoids Model Endothelial Cell Responses to Injury
Ament, A.-L., Heiner, M., Hessler, M. C., Alexopoulos, I., Steeg, K., Gärtner, U., Vazquez-Armendariz, A. I., & Herold, S. (2025) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2023-0373ma · Cited by 17 · see citing works
- Authors
- Tan, Q., Choi, K. M., Sicard, D., & Tschumperlin, D. J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Tschumperlin, Daniel J.
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 113
- Pages
- 118-132
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC5121055
- OpenAlex
- W2543020994
- Cited by
- 191
- References
- 87
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 27 · 2023: 23 · 2022: 28 · 2021: 33 · 2020: 19 · 2019: 11 · 2018: 14 · 2017: 8
- FWCI
- 12.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (HL092961)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Keywords
- airway organoids, lung regeneration, bronchial epithelial cells, lung fibroblasts, lung microvascular endothelial cells, 3D cell culture, self-organization, branching morphogenesis, YAP/TAZ signaling, epithelial plasticity, chronic lung disease, cell therapy, disease modeling
- MeSH terms
- Adult, Animals, Cell Differentiation, Cell Line, Cells, Cultured, Epithelial Cells, Humans, Lung, Organ Culture Techniques, Organoids, Regeneration, Tissue Engineering, Organogenesis, Endothelial Cells, Mice, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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