Impaired neurite development associated with mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of children with autism spectrum disorder.
Impaired neurite development associated with mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of children with autism spectrum disorder.
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DOI：
10.1016/j.bbrep.2018.09.004
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发表时间：
2018-12
影响因子：
2.7
通讯作者：
Nonaka K
中科院分区：
文献类型：
--
作者：
Nguyen HTN;Kato H;Masuda K;Yamaza H;Hirofuji Y;Sato H;Pham TTM;Takayama F;Sakai Y;Ohga S;Taguchi T;Nonaka K
自闭症谱系障碍（ASD）是一种高度异质性的神经发育障碍，其特征是社会互动受损，限制性兴趣和重复刻板行为。在ASD发病机制的各种机制中，多巴胺能信号传导和线粒体功能障碍被认为是ASD儿童的核心症状。然而，只有少数研究使用患者源性干细胞和体外分化的神经元进行了针对ASD中多巴胺能神经元（DN）与线粒体之间病理联系的研究。人脱落乳牙干细胞（SHED）是存在于脱落乳牙牙髓中的神经嵴来源的间充质干细胞;这些细胞可以在体外分化为多巴胺能神经元（DN）。本研究旨在通过使用SHED作为疾病或患者特异性细胞模型来研究DN的发展与ASD中线粒体之间的病理联系。从三名ASD儿童和三名典型发育儿童获得的SHED分化为DN，并对这些细胞的神经生物学进行了检查。来自ASD儿童的DN表现出受损的神经突生长和分支，与线粒体膜电位、ATP产生、神经突内线粒体数量、单位细胞面积线粒体数量和细胞内钙水平降低相关。此外，受损的轴突生长和分支的ASD衍生的DN没有改善脑源性神经营养因子（BDNF），这表明在ASD的BDNF信号通路的损害。这些结果意味着这些儿童的脑内多巴胺产生可能减少了。人类乳牙自发脱落的最早年龄约为6岁，并且可以无创地收集SHED。我们的研究结果表明，从ASD儿童中获得的SHED源性DN的体外分析提供了神经生物学信息，这些信息可能有助于确定ASD早期的治疗策略。自闭症患者牙髓干细胞向多巴胺能神经元分化的研究。与对照组相比，这些神经元的神经突发育受损。这种损伤与线粒体功能障碍有关。牙髓干细胞可能有助于建立治疗自闭症的策略。
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restrictive interests, and repetitive stereotypic behaviors. Among the various mechanisms underlying the pathogenesis of ASD, dysfunctions of dopaminergic signaling and mitochondria have been hypothesized to explain the core symptoms of children with ASD. However, only a few studies focusing on the pathological association between dopaminergic neurons (DN) and mitochondria in ASD have been performed using patient-derived stem cells and in vitro differentiated neurons. Stem cells from human exfoliated deciduous teeth (SHED) are neural crest-derived mesenchymal stem cells present in the dental pulp of exfoliated deciduous teeth; these cells can differentiate into dopaminergic neurons (DN) in vitro. This study aimed to investigate the pathological association between development of DN and mitochondria in ASD by using SHED as a disease- or patient-specific cellular model. The SHED obtained from three children with ASD and three typically developing children were differentiated into DN, and the neurobiology of these cells was examined. The DN derived from children with ASD showed impaired neurite outgrowth and branching, associated with decreased mitochondrial membrane potential, ATP production, number of mitochondria within the neurites, amount of mitochondria per cell area and intracellular calcium level. In addition, impaired neurite outgrowth and branching of ASD-derived DN were not improved by brain-derived neurotrophic factor (BDNF), suggesting impairment of the BDNF signaling pathway in ASD. These results imply that intracerebral dopamine production may have decreased in these children. The earliest age at which deciduous teeth spontaneously exfoliate in humans, and SHED can be noninvasively collected, is approximately 6 years. Our results suggest that in vitro analysis of SHED-derived DN obtained from children with ASD provides neurobiological information that may be useful in determining treatment strategies in the early stages of ASD. Dental pulp stem cells of autistic patient differentiate into dopaminergic neurons. These neurons show impaired neurite development compared with those from controls. This impairment is associated with mitochondrial dysfunction. Dental pulp stem cells may help establish treatment strategies against autism.
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影响因子：
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来自人类脱落乳牙的干细胞可以分化为多巴胺能神经元样细胞。
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