Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Francois Renault Mihara
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Shigeki Ohta
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Kimiko Fukuda
Department of Biological Science, Tokyo Metropolitan University, Tokyo, Japan
Kenji Kurosawa
Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan
Wado Akamatsu
Department of Physiology, Keio University School of Medicine, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan
Tsukasa Sanosaka
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Jun Kohyama
Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Kanehiro Hayashi
Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
Takao Takahashi
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
Joanna Wysocka
Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
Kenjiro Kosaki
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs). We found that expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs compared to control iPSC-NCCs. Consistently, CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo. These results support the historical inference that CHARGE syndrome patients exhibit defects in neural crest migration, and provide the first successful application of patient-derived iPSCs in modeling craniofacial disorders.
