TY - JOUR
T1 - CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations
AU - Okuno, Hironobu
AU - Mihara, Francois Renault
AU - Ohta, Shigeki
AU - Fukuda, Kimiko
AU - Kurosawa, Kenji
AU - Akamatsu, Wado
AU - Sanosaka, Tsukasa
AU - Kohyama, Jun
AU - Hayashi, Kanehiro
AU - Nakajima, Kazunori
AU - Takahashi, Takao
AU - Wysocka, Joanna
AU - Kosaki, Kenjiro
AU - Okano, Hideyuki
N1 - Funding Information:
We would like to thank Professors Shinya Yamanaka (CiRA, Kyoto University) and Norio Nakatsuji (Kyoto University) for providing 201B7 iPSCs and KhES1 cells, respectively. We are grateful to Yu Yamaguchi for technical assistance and suggestions, and to all members of the Okano laboratory for their encouragement and support. We thank Douglas Sipp (Keio University) for invaluable comments regarding the manuscript. This work was supported by funding from the Project for the Realization of Regenerative Medicine; Support for the Core Institutes for iPS Cell Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT; to H Okano); and a Grant-in- Aid for the Global COE Program from MEXT to Keio University. This work was also supported by a Grant-in-Aid for Young Scientists (B) from MEXT (project number: 26860823), a Keio University Grant-in-Aid for the Encouragement of Young Medical Scientists to H Okuno., and by a Grant-in-Aid for Scientific Research on Innovative Areas from MEXT to K Nakajima (project number: JP16H06482). H Okano is a scientific consultant for SanBio, Co. Ltd. and K Pharma Inc. Keio University School of Medicine Grant-in-Aid for the Encouragement of Young Medical Scientists Hironobu Okuno. Keio University School of Medicine Grant-in-Aid for the Encouragement of Young Medical Scientists Hironobu Okuno Ministry of Education, Culture, Sports, Science, and Technology Project for Realization of Regenerative Medicine and Support for Core Institutes for iPSC research Hideyuki Okano Ministry of Education, Culture, Sports, Science, and Technology A Grant -in-Aid for the Global COE program Hironobu Okuno Hideyuki Okano Ministry of Education, Culture, Sports, Science, and Technology A Grant-in-Aid for Young Scientists (B) Hironobu Okuno Ministry of Education, Culture, Sports, Science, and Technology A Grant-in-Aid for Scientifc Reserch on Innovative Areas Kazunori Nakajima Ministry of Education, Culture, Sports, Science, and Technology Support for Core Institutes fro iPS Cell Research Hideyuki Okano The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Funding Information:
We would like to thank Professors Shinya Yamanaka (CiRA, Kyoto University) and Norio Nakatsuji (Kyoto University) for providing 201B7 iPSCs and KhES1 cells, respectively. We are grateful to Yu Yamaguchi for technical assistance and suggestions, and to all members of the Okano laboratory for their encouragement and support. We thank Douglas Sipp (Keio University) for invaluable comments regarding the manuscript. This work was supported by funding from the Project for the Realization of Regenerative Medicine; Support for the Core Institutes for iPS Cell Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT; to H Okano); and a Grant-in-Aid for the Global COE Program from MEXT to Keio University. This work was also supported by a Grant-in-Aid for Young Scientists (B) from MEXT (project number: 26860823), a Keio University Grant-in-Aid for the Encouragement of Young Medical Scientists to H Okuno., and by a Grant-in-Aid for Scientific Research on Innovative Areas from MEXT to K Nakajima (project number: JP16H06482). H Okano is a scientific consultant for SanBio,Co. Ltd. and K Pharma Inc.
Publisher Copyright:
© Okuno et al.
PY - 2017/11/28
Y1 - 2017/11/28
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.21114
DO - 10.7554/eLife.21114
M3 - Article
C2 - 29179815
AN - SCOPUS:85036494994
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e21114
ER -