Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids
(2023) In Life Science Alliance 6(8).- Abstract
Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5-/KRT17+ aberrant basaloid phenotype recently identified in the lungs of... (More)
Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5-/KRT17+ aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.
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- author
- Ptasinski, Victoria LU ; Monkley, Susan J. ; Öst, Karolina ; Tammia, Markus ; Alsafadi, Hani N. LU ; Overed-Sayer, Catherine ; Hazon, Petra ; Wagner, Darcy E. LU and Murray, Lynne A.
- organization
-
- LU Profile Area: Light and Materials
- LTH Profile Area: Nanoscience and Semiconductor Technology
- NanoLund: Centre for Nanoscience
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Lung Bioengineering and Regeneration (research group)
- WCMM-Wallenberg Centre for Molecular Medicine
- Stem Cell Center
- LTH Profile Area: Engineering Health
- LUCC: Lund University Cancer Centre
- publishing date
- 2023-08-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Life Science Alliance
- volume
- 6
- issue
- 8
- article number
- e202201853
- publisher
- Rockefeller University Press
- external identifiers
-
- pmid:37230801
- scopus:85160454920
- ISSN
- 2575-1077
- DOI
- 10.26508/lsa.202201853
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2023 Ptasinski et al.
- id
- 282c4a21-2944-49cc-b147-0761344fab3a
- date added to LUP
- 2023-06-05 13:15:14
- date last changed
- 2024-04-19 22:36:38
@article{282c4a21-2944-49cc-b147-0761344fab3a, abstract = {{<p>Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5-/KRT17+ aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.</p>}}, author = {{Ptasinski, Victoria and Monkley, Susan J. and Öst, Karolina and Tammia, Markus and Alsafadi, Hani N. and Overed-Sayer, Catherine and Hazon, Petra and Wagner, Darcy E. and Murray, Lynne A.}}, issn = {{2575-1077}}, language = {{eng}}, month = {{08}}, number = {{8}}, publisher = {{Rockefeller University Press}}, series = {{Life Science Alliance}}, title = {{Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids}}, url = {{http://dx.doi.org/10.26508/lsa.202201853}}, doi = {{10.26508/lsa.202201853}}, volume = {{6}}, year = {{2023}}, }