CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations
CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations
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DOI：
10.7554/elife.21114
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发表时间：
2017-11-28
期刊：
影响因子：
7.7
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Okuno, Hironobu;Mihara, Francois Renault;Okano, Hideyuki
CHARGE综合征是由染色质重塑因子CHD 7的杂合突变引起的，其特征在于一组畸形，根据临床依据，历史上推测是由胚胎发育期间神经嵴形成缺陷引起的。为了更好地描述CHARGE综合征中的神经嵴缺陷，我们从两名具有典型综合征表现的患者中产生了诱导多能干细胞（iPSC），并表征了从这些iPSC（iPSC-NCC）体外分化的神经嵴细胞。我们发现，与对照iPSC-NCC相比，CHARGE iPSC-NCC中与细胞迁移相关的基因表达发生了改变。一致地，CHARGE iPSC-NCC在体外显示有缺陷的分层、迁移和运动性，并且它们在卵中的移植揭示了鸡胚中的总体缺陷的迁移活性。这些结果支持CHARGE综合征患者表现出神经嵴迁移缺陷的历史推断，并提供了患者来源的iPSC在颅面疾病建模中的首次成功应用。
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.