GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Abstract

Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC related pathologies.

Data availability

Sequencing data was deposited in GEO: GSE160871

The following data sets were generated

Article and author information

Author details

  1. Rafael Jesus Fernandez III

    Medical Scientist Training Program, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9295-4810
  2. Zachary J G Gardner

    Medical Scientist Training Program, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Katherine J Slovik

    Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Derek C Liberti

    Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2991-9283
  5. Katrina N Estep

    Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Wenli Yang

    Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  7. Qijun Chen

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  8. Garrett T Santini

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  9. Javier V Perez

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  10. Sarah Root

    College of Arts and Sciences and Vagelos Scholars Program, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  11. Ranvir Bhatia

    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  12. John W Tobias

    Penn Genomic Analysis Core, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  13. Apoorva Babu

    Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  14. Michael P Morley

    Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  15. David B Frank

    Penn-CHOP Lung Biology Institute, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    No competing interests declared.
  16. Edward E Morrisey

    Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    Edward E Morrisey, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5785-1939
  17. Christopher J Lengner

    Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States
    For correspondence
    lengner@vet.upenn.edu
    Competing interests
    No competing interests declared.
  18. F Brad Johnson

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    johnsonb@pennmedicine.upenn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7443-7227

Funding

National Institute on Aging (R21AG054209)

  • Christopher J Lengner
  • F Brad Johnson

National Institute on Aging (5T32AG000255)

  • Rafael Jesus Fernandez III

Team Telomere/Penn Orphan Disease Center

  • Christopher J Lengner
  • F Brad Johnson

National Heart, Lung, and Blood Institute (R01HL148821)

  • Christopher J Lengner
  • F Brad Johnson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Weiwei Dang, Baylor College of Medicine, United States

Publication history

  1. Received: October 28, 2020
  2. Accepted: May 11, 2022
  3. Accepted Manuscript published: May 13, 2022 (version 1)

Copyright

© 2022, Fernandez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rafael Jesus Fernandez III
  2. Zachary J G Gardner
  3. Katherine J Slovik
  4. Derek C Liberti
  5. Katrina N Estep
  6. Wenli Yang
  7. Qijun Chen
  8. Garrett T Santini
  9. Javier V Perez
  10. Sarah Root
  11. Ranvir Bhatia
  12. John W Tobias
  13. Apoorva Babu
  14. Michael P Morley
  15. David B Frank
  16. Edward E Morrisey
  17. Christopher J Lengner
  18. F Brad Johnson
(2022)
GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells
eLife 11:e64430.
https://doi.org/10.7554/eLife.64430

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