CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations

eLife

Tsukasa Sanosaka¹  Hideyuki Okano²  Takao Takahashi³  Kazunori Nakajima³  Kimiko Fukuda⁴  Kenjiro Kosaki⁵  Joanna Wysocka⁶  Kanehiro Hayashi⁷  Shigeki Ohta⁷  Jun Kohyama⁷  Francois Renault Mihara⁷  Wado Akamatsu⁷  Hironobu Okuno⁷  Kenji Kurosawa⁸ 

[1] Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan;Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States;Department of Anatomy, Keio University School of Medicine, Tokyo, Japan;Department of Biological Science, Tokyo Metropolitan University, Tokyo, Japan;Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States;Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan;Department of Physiology, Keio University School of Medicine, Tokyo, Japan;Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan;

关键词: CHD7;    CHARGE syndrome;    induced pluripotent stem cells;    neural crest;    cell migration;    disease modeling;   

DOI  :  10.7554/eLife.21114

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown