Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Zachary JG Gardner
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Katherine J Slovik
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Katrina N Estep
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Wenli Yang
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Qijun Chen
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Garrett T Santini
Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Javier V Perez
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Sarah Root
College of Arts and Sciences and Vagelos Scholars Program, University of Pennsylvania, Philadelphia, United States
Ranvir Bhatia
Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
John W Tobias
Penn Genomic Analysis Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Apoorva Babu
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, United States
Michael P Morley
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, United States
David B Frank
Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, United States; Division of Pediatric Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, United States
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Institute on Aging, University of Pennsylvania, Philadelphia, United States
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 induced pluripotent stem cell-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.
