Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination.
Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination.
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DOI：
10.1002/ana.23606
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发表时间：
2012-09
影响因子：
11.2
通讯作者：
Selkirk, Stephen M.
中科院分区：
文献类型：
--
作者：
Caprariello, Andrew V.;Mangla, Saisho;Miller, Robert H.;Selkirk, Stephen M.
多发性硬化症（MS）是一种中枢神经系统脱髓鞘疾病，其表现为可能反映不同致病机制的可变病理。现有的MS动物模型通过局部注射胶质毒素或用髓鞘相关肽刺激免疫系统来诱导病理学。在这些模型中，主要的细胞靶点均未得到充分表征，尽管脱髓鞘是MS的标志性病理特征，但尚不清楚这在多大程度上反映了局部少突胶质细胞损失。为了明确识别少突胶质细胞死亡的影响，在没有炎症刺激的情况下，我们开发了一种方法，实验诱导程序性细胞死亡选择性成熟的少突胶质细胞和评估脱髓鞘，免疫刺激和神经胶质增生的影响。相对于观察到的MS病理，讨论了所得的病理。在成年大鼠脑中使用慢病毒诱导少突胶质细胞凋亡，以在髓鞘碱性蛋白（MBP）启动子的转录控制下表达实验诱导型胱天蛋白酶9（iCP9）cDNA，其是少突胶质细胞特异性的。通过向侧脑室远端注射小分子二聚体实现iCP9的激活，导致局部急性少突胶质细胞凋亡。诱导的少突胶质细胞凋亡导致快速脱髓鞘和强大的，局部的小胶质细胞活化的情况下，外周免疫细胞浸润。病变边界显示髓鞘层保存和降解，而病变核心脱髓鞘，但仅部分清除髓鞘碎片。这导致了少突胶质细胞祖细胞库的局部增殖和动员。这种方法提供了一种新的模型，以了解病理变化，从本地化的髓鞘少突胶质细胞凋亡。它提供了第一个直接证据，即少突胶质细胞中细胞凋亡的启动足以引起快速脱髓鞘、神经胶质增生和小胶质细胞反应，从而导致与MS病变子集具有某些病理特征的病变。
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation and gliosis. The resulting pathology is discussed relative to observed MS pathologies. Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally-inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein (MBP), which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, while lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis and microglia response that result in lesions that share some pathological characteristics with a subset of MS lesions.
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影响因子：
11.2
作者：
Breij, Esther C. W.;Brink, Bianca P.;Boe, Lars
通讯作者：
Boe, Lars
影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G
影响因子：
14.5
作者：
Stadelmann, C;Ludwin, S;Lassmann, H
通讯作者：
Lassmann, H
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.5
作者：
Lucchinetti, C;Brück, W;Lassmann, H
通讯作者：
Lassmann, H