Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease
Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease
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DOI：
10.1093/brain/awaa080
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发表时间：
2020-05-01
期刊：
影响因子：
14.5
通讯作者：
Edgar, Julia M.
中科院分区：
文献类型：
--
作者：
Gruenenfelder, Fredrik, I;McLaughlin, Mark;Edgar, Julia M.
Pelizaeus-Merzbacher病是一种致命的X连锁脑白质营养不良，由PLP 1基因突变引起，该基因在CNS中由少突胶质细胞表达。疾病的发作、症状和死亡率范围很广，这取决于突变的性质，因此也取决于CNS髓鞘形成不足的程度。在缺乏有效治疗的情况下，直接细胞移植到CNS中以恢复髓鞘已经在具有发育性髓鞘形成失败的严重形式的疾病的动物模型中进行了测试，并且最近在由于PLP 1基因中的点突变而具有早期疾病发作的严重受影响的患者中进行了测试，并且通过MRI没有髓鞘。PLP 1重复突变是Pelizaeus-Merzbacher病最常见的病因，由于缺乏尸检材料，其病理学定义不清。为了解决这个问题，我们检查了两个老年患者的PLP 1重复的整体综合征，包括终末期病理，表明一个复杂的疾病，涉及髓鞘形成障碍，脱髓鞘和轴突变性。使用相应的Plp 1转基因小鼠模型，然后我们测试了移植的神经干细胞在PLP过表达的背景下恢复髓鞘的能力。虽然发育髓鞘形成和轴突覆盖的内源性少突胶质细胞是广泛的，如使用电子显微镜（n = 3，在每个四个端点）和免疫染色（n = 3，在每个四个端点），野生型神经前体，移植到新生儿突变体的大脑，能够有效地竞争和取代有缺陷的髓鞘（n = 2，在每个四个端点）。这些数据证明了神经干细胞疗法在PLP 1基因重复突变患者中恢复正常髓鞘形成和保护轴突的潜力，并进一步为干细胞移植对其他具有“正常”发育髓鞘形成的致命脑白质营养不良的益处提供了原理证明。
Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with 'normal' developmental myelination.