Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model.
Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model.
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人类唐氏综合症干细胞模型中 CXADR 三倍体引起的神经嵴迁移缺陷
DOI：
10.1038/s41419-022-05481-6
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发表时间：
2022-12-05
影响因子：
9
通讯作者：
Li, Weiqiang
中科院分区：
文献类型：
--
作者：
Liu, Huanyao;Huang, Shanshan;Wang, Weijia;Wang, Huiyan;Huang, Weijun;Zhai, Zhichen;Wang, Ding;Fan, Yubao;Sun, Jiaqi;Li, Dairui;Chiu, Weicheng;Lai, Xingqiang;Zeng, Jixiao;Ke, Qiong;Wang, Tao;Xiang, Andy Peng;Yuan, Yong;Zhang, Xinchun;Li, Weiqiang
唐氏综合征（DS）是活产婴儿中最常见的染色体异常，由21号染色体三体引起。大多数患有DS的个体显示颅面畸形，包括头骨、上颌骨和下颌骨的尺寸减小。然而，其潜在的发病机制仍在很大程度上未知。由于颅面骨骼主要由神经嵴形成，因此神经嵴发育缺陷是否与DS患者的颅面异常有关还需要进一步研究。在这里，我们使用仙台病毒载体成功地衍生了DS特异性人诱导多能干细胞（hiPSC）。当诱导DS-hiPSC分化为神经嵴时，我们发现21三体（T21）不影响细胞增殖或凋亡。然而，分化的细胞的迁移能力显着受损，从而导致在一个实质上较低的数量的迁移后颅神经嵴干细胞（NCSC）在DS组比对照组。我们进一步发现，迁移缺陷可能部分归因于柯萨奇病毒和腺病毒受体基因（CXADR;粘附蛋白）在DS组细胞中的三倍，因为CXADR的敲除基本上恢复了DS组细胞的迁移能力和迁移后NCSC的产生。因此，神经嵴细胞的迁移缺陷可能是DS患者颅面畸形的根本原因，这可能表明治疗干预的潜在目标，以改善DS的颅面或其他神经嵴相关异常。
Down syndrome (DS) is the most common chromosomal abnormality in live-born infants and is caused by trisomy of chromosome 21. Most individuals with DS display craniofacial dysmorphology, including reduced sizes of the skull, maxilla, and mandible. However, the underlying pathogenesis remains largely unknown. Since the craniofacial skeleton is mainly formed by the neural crest, whether neural crest developmental defects are involved in the craniofacial anomalies of individuals with DS needs to be investigated. Here, we successfully derived DS-specific human induced pluripotent stem cells (hiPSCs) using a Sendai virus vector. When DS-hiPSCs were induced to differentiate into the neural crest, we found that trisomy 21 (T21) did not influence cell proliferation or apoptosis. However, the migratory ability of differentiated cells was significantly compromised, thus resulting in a substantially lower number of postmigratory cranial neural crest stem cells (NCSCs) in the DS group than in the control group. We further discovered that the migration defects could be partially attributed to the triplication of the coxsackievirus and adenovirus receptor gene (CXADR; an adhesion protein) in the DS group cells, since knockdown of CXADR substantially recovered the cell migratory ability and generation of postmigratory NCSCs in the DS group. Thus, the migratory deficits of neural crest cells may be an underlying cause of craniofacial dysmorphology in individuals with DS, which may suggest potential targets for therapeutic intervention to ameliorate craniofacial or other neural crest-related anomalies in DS.
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影响因子：
1.4
作者：
Brandt, BR;Rosen, I
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影响因子：
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作者：
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影响因子：
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作者：
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