GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells
- University of Pennsylvania, United States
- Children's Hospital of Philadelphia, United States
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
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Transcriptional profiling of short telomere iPS-derived sorted SFTPC+ iAT2 cells.NCBI Gene Expression Omnibus, GSE160871.
Article and author information
Author details
Rafael Jesus Fernandez III
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.
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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Further reading
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