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Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids

Ptasinski, Victoria LU ; Monkley, Susan J. ; Öst, Karolina ; Tammia, Markus ; Alsafadi, Hani N. LU orcid ; Overed-Sayer, Catherine ; Hazon, Petra ; Wagner, Darcy E. LU orcid and Murray, Lynne A. (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
; ; ; ; ; ; ; and
organization
publishing date
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}},
}