Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells
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Abstract
The pathogenesis of idiopathic pulmonary fibrosis (IPF), an intractable interstitial lung disease, is unclear. Recessive mutations in some genes implicated in Hermansky-Pudlak syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity that is similar to IPF. We previously reported that HPS1 −/− embryonic stem cell-derived 3D lung organoids showed fibrotic changes. Here, we show that the introduction of all HPS mutations associated with HPSIP promotes fibrotic changes in lung organoids, while the deletion of HPS8, which is not associated with HPSIP, does not. Genome-wide expression analysis revealed the upregulation of interleukin-11 (IL-11) in epithelial cells from HPS mutant fibrotic organoids. IL-11 was detected predominantly in type 2 alveolar epithelial cells in end-stage IPF, but was expressed more broadly in HPSIP. Finally, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in HPS4 −/− organoids, suggesting IL-11 as a therapeutic target. hPSC-derived 3D lung organoids are, therefore, a valuable resource to model fibrotic lung disease.
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iPSCs can be derived from adult patient cells, including from patients with monogenic lung disease or, in the case of PF, a genetic predisposition to developing lung disease.
“iPSCs can also be derived from adult patient cells, including from patients with monogenic lung disease or, in the case of PF, a genetic predisposition to developing lung disease (Strikoudis et al., 2019).”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Strikoudis et al., 2019
Major advances in protocols to generate alveolar organoids derived from genetically editable human iPSCs are paving the way for disease modelling and future functional regeneration of the distal lung.
“However, major advances in the development of protocols to generate alveolar organoids derived from geneticallyeditable (e.g. CRISPR-Cas 9) human induced pluripotent stem cells (iPSCs) are now paving the way for disease modelling, as well as the future functional regeneration of the distal lung.”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Strikoudis et al., 2019
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References 107 · Cited by 242
- Authors
- Strikoudis, A., Cieślak, A., Loffredo, L., Chen, Y.-W., Patel, N., Saqi, A., Lederer, D. J., & Snoeck, H.-W.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Snoeck, Hans-Willem
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 27
- Issue
- 12
- Pages
- 3709-3723.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6594401
- OpenAlex
- W2948122886
- Cited by
- 242
- References
- 107
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 24 · 2023: 47 · 2022: 41 · 2021: 46 · 2020: 34 · 2019: 4
- FWCI
- 22.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH Office of the Director
- National Heart, Lung, and Blood Institute
- New York Stem Cell Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- idiopathic pulmonary fibrosis, Hermansky-Pudlak syndrome, human pluripotent stem cells, HPS1, interleukin-11, alveolar type II cells, fibrosis, disease modeling, therapeutic target
- MeSH terms
- Adult, Aged, Carrier Proteins, Female, Humans, Male, Middle Aged, Models, Biological, Organ Culture Techniques, Organoids, Pulmonary Fibrosis, Interleukin-11, Guanine Nucleotide Exchange Factors, Hermanski-Pudlak Syndrome, Pluripotent Stem Cells
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