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Human brain organoid-on-a-chip to model prenatal nicotine exposure†
Lab on a Chip ( IF 6.1 ) Pub Date : 2018-02-07 00:00:00 , DOI: 10.1039/c7lc01084b Yaqing Wang 1, 2, 3, 4, 5 , Li Wang 1, 2, 3, 4, 5 , Yujuan Zhu 1, 2, 3, 4, 5 , Jianhua Qin 1, 2, 3, 4, 5
Lab on a Chip ( IF 6.1 ) Pub Date : 2018-02-07 00:00:00 , DOI: 10.1039/c7lc01084b Yaqing Wang 1, 2, 3, 4, 5 , Li Wang 1, 2, 3, 4, 5 , Yujuan Zhu 1, 2, 3, 4, 5 , Jianhua Qin 1, 2, 3, 4, 5
Affiliation
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Nicotine has been recognized to trigger various neuronal disabilities in the fetal brain and long-lasting behavioral deficits in offspring. However, further understanding of fetal brain development under nicotine exposure is challenging due to the limitations of existing animal models. Here, we create a new brain organoid-on-a-chip system derived from human induced pluripotent stem cells (hiPSCs) that allows us to model neurodevelopmental disorders under prenatal nicotine exposure (PNE) at early stages. The brain organoid-on-a-chip system facilitates 3D culture, in situ neural differentiation, and self-organization of brain organoids under continuous perfused cultures in a controlled manner. The generated brain organoids displayed well-defined neural differentiation, regionalization, and cortical organization, which recapitulates the key features of the early stages of human brain development. The brain organoids exposed to nicotine exhibited premature neuronal differentiation with enhanced expression of the neuron marker TUJ1. Brain regionalization and cortical development were disrupted in the nicotine-treated organoids identified by the expressions of forebrain (PAX6 and FOXG1), hindbrain (PAX2 and KROX20) and cortical neural layer (preplate TBR1 and deep-layer CTIP2) markers. Moreover, the neurite outgrowth showed abnormal neuronal differentiation and migration in nicotine-treated brain organoids. These results suggest that nicotine exposure elicits impaired neurogenesis in early fetal brain development during gestation. The established brain organoid-on-a-chip system provides a promising platform to model neurodevelopmental disorders under environmental exposure, which can be extended for applications in brain disease studies and drug testing.
中文翻译：
人脑芯片上的类器官模拟产前尼古丁暴露†
尼古丁已被认为会引发胎儿脑部各种神经元残疾和后代长期的行为缺陷。然而，由于现有动物模型的局限性，对尼古丁暴露下胎儿大脑发育的进一步了解具有挑战性。在这里，我们创建了一个新的从人类诱导的多能干细胞（hiPSC）衍生出来的脑片上类器官系统，该系统使我们能够在产前尼古丁暴露（PNE）下模拟神经发育障碍。大脑芯片上的类器官系统可促进3D原位培养神经分化和在连续灌注培养下以受控方式进行的脑器官的自组织。生成的脑类器官显示出明确的神经分化，区域化和皮质组织，从而概括了人类大脑发育早期的关键特征。暴露于尼古丁的脑类器官表现出神经元过早分化，神经元标记TUJ1的表达增强。通过前脑（PAX6和FOXG1），后脑（PAX2和KROX20）和皮质神经层（预平板TBR1和深层CTIP2）标记物的表达，烟碱处理过的类器官中的脑区域化和皮质发育受到破坏。此外，神经突生长在尼古丁治疗的脑类器官中显示出异常的神经元分化和迁移。这些结果表明，尼古丁暴露会引起妊娠早期胎儿大脑发育中的神经发生受损。已建立的脑片上类器官系统提供了一个有前途的平台，可以在环境暴露下对神经发育障碍进行建模，该平台可以扩展到脑疾病研究和药物测试中。
更新日期：2018-02-07
中文翻译：
人脑芯片上的类器官模拟产前尼古丁暴露†
尼古丁已被认为会引发胎儿脑部各种神经元残疾和后代长期的行为缺陷。然而，由于现有动物模型的局限性，对尼古丁暴露下胎儿大脑发育的进一步了解具有挑战性。在这里，我们创建了一个新的从人类诱导的多能干细胞（hiPSC）衍生出来的脑片上类器官系统，该系统使我们能够在产前尼古丁暴露（PNE）下模拟神经发育障碍。大脑芯片上的类器官系统可促进3D原位培养神经分化和在连续灌注培养下以受控方式进行的脑器官的自组织。生成的脑类器官显示出明确的神经分化，区域化和皮质组织，从而概括了人类大脑发育早期的关键特征。暴露于尼古丁的脑类器官表现出神经元过早分化，神经元标记TUJ1的表达增强。通过前脑（PAX6和FOXG1），后脑（PAX2和KROX20）和皮质神经层（预平板TBR1和深层CTIP2）标记物的表达，烟碱处理过的类器官中的脑区域化和皮质发育受到破坏。此外，神经突生长在尼古丁治疗的脑类器官中显示出异常的神经元分化和迁移。这些结果表明，尼古丁暴露会引起妊娠早期胎儿大脑发育中的神经发生受损。已建立的脑片上类器官系统提供了一个有前途的平台，可以在环境暴露下对神经发育障碍进行建模，该平台可以扩展到脑疾病研究和药物测试中。
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