Human IPSC-Derived Model to Study Myelin Disruption.
Human IPSC-Derived Model to Study Myelin Disruption.
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DOI：
10.3390/ijms22179473
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发表时间：
2021-08-31
影响因子：
5.6
通讯作者：
Pamies D
中科院分区：
文献类型：
--
作者：
Chesnut M;Paschoud H;Repond C;Smirnova L;Hartung T;Zurich MG;Hogberg HT;Pamies D
髓磷脂对中枢神经系统至关重要，其破坏与大量神经发育和神经退行性疾病有关。在人类和啮齿动物少突胶质细胞之间观察到的差异使得动物不足以模拟这些疾病。虽然开发少突胶质细胞和有髓鞘轴突的人类体外模型一直是一个巨大的挑战，但现在可以获得来自iPSC的3D细胞培养物，并且能够部分重现髓鞘形成过程。我们之前已经开发了一种人类iPSC衍生的3D脑类器官模型（也称为BrainSpheres），该模型包含高百分比的有髓鞘轴突，并且具有高度可重复性。在这里，我们通过应用多个读数来研究髓鞘形成中断，进一步完善了这项技术。通过定量共定位髓鞘碱性蛋白（MBP）与神经丝蛋白以及蛋白脂质蛋白1（PLP 1）的免疫染色/共聚焦显微镜评估髓鞘。PLP 1的水平也通过蛋白质印迹进行评估。我们在一项系统综述中鉴定了能够通过破坏髓鞘诱导发育神经毒性的化合物，以评估我们的BrainSphere模型用于髓鞘形成/脱髓鞘过程研究的相关性。结果表明，阳性参比化合物（cuprizone）和测试的三种潜在髓鞘破坏剂中的两种（双酚A、磷酸三（1，3-二氯-2-丙基）酯，但不是甲基汞）减少髓鞘形成，而布洛芬（阴性对照）没有影响。在这里，我们定义了一种方法，可以量化髓鞘破坏，并提供化学诱导的髓鞘破坏的参考化合物。
Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption.
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影响因子：
4.6
作者：
Dach K;Bendt F;Huebenthal U;Giersiefer S;Lein PJ;Heuer H;Fritsche E
通讯作者：
Fritsche E
影响因子：
25
作者：
Barak, Boaz;Zhang, Zicong;Feng, Guoping
通讯作者：
Feng, Guoping
DOI：
10.1093/brain/awx012
发表时间：
2017-04-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Clark AJ;Kaller MS;Galino J;Willison HJ;Rinaldi S;Bennett DLH
通讯作者：
Bennett DLH
DOI：
10.1080/15374416.2017.1417860
发表时间：
2018-03
期刊：
Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53
影响因子：
--
作者：
Danielson ML;Bitsko RH;Ghandour RM;Holbrook JR;Kogan MD;Blumberg SJ
通讯作者：
Blumberg SJ
影响因子：
8.2
作者：
Andersen, SL
通讯作者：
Andersen, SL