Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease

Konstantinos Dionysios Alysandratos, Scott J. Russo, Anton Petcherski, Evan P. Taddeo, Rebeca Acín-Pérez, Carlos Villacorta-Martin, J. C. Jean, Surafel Mulugeta, Luis R. Rodriguez, Benjamin C. Blum, Ryan M. Hekman, Olivia T. Hix, Kasey Minakin, Marall Vedaie, Seunghyi Kook, Andrew M. Tilston-Lunel, Xaralabos Varelas, Jennifer A. Wambach, F. Sessions Cole, Aaron HamvasLisa R. Young, Marc Liesa, Andrew Emili, Susan H. Guttentag, Orian S. Shirihai, Michael F. Beers*, Darrell N. Kotton

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.

Original languageEnglish (US)
Article number109636
JournalCell reports
Volume36
Issue number9
DOIs
StatePublished - Aug 31 2021

Keywords

  • NF-κB
  • autophagy
  • bioenergetics
  • iPSC-derived alveolar epithelial type 2 cells
  • idiopathic pulmonary fibrosis
  • induced pluripotent stem cells
  • interstitial lung disease
  • metabolic reprogramming
  • proteostasis
  • surfactant protein C

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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