Myelin regulatory factor drives remyelination in multiple sclerosis
Myelin regulatory factor drives remyelination in multiple sclerosis
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DOI：
10.1007/s00401-017-1741-7
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发表时间：
2017-09-01
影响因子：
12.7
通讯作者：
Tetzlaff, Wolfram
中科院分区：
文献类型：
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作者：
Duncan, Greg J.;Plemel, Jason R.;Tetzlaff, Wolfram
尽管在大多数多发性硬化（MS）病变中存在少突胶质前体细胞（OPC），但在大多数MS病变中再髓鞘化是有限的。这一观察结果导致了这样的观点，即OPCs不能完全分化是髓鞘再生失败的基础。OPC分化需要复杂的转录调控，这可能在慢性MS病变中被破坏。一些转录因子的表达已被区别比较髓鞘再生病变和难治性髓鞘再生病变。特别是，少突胶质细胞转录因子髓鞘调节因子（MYRF）是必不可少的髓鞘形成过程中的发展，但其作用在髓鞘再生和MS病变的表达是未知的。为了了解MYRF在髓鞘再生过程中的作用，我们对溶血卵磷脂诱导的小鼠胼胝体脱髓鞘后的OPCs进行了基因命运定位，并确定MYRF在新的少突胶质细胞中表达。OPC特异性Myrf缺失并没有改变这些细胞的招募或增殖脱髓鞘后，但减少了新的谷胱甘肽S-转移酶pi阳性少突胶质细胞的密度。随后在脊髓和胼胝体的髓鞘再生是高度受损后Myrf删除OPCs。个别OPC衍生的少突胶质细胞，在响应脱髓鞘，表现出很小的能力，表达髓鞘蛋白Myrf删除后。总的来说，这些数据表明，在髓鞘再生过程中，MYRF在少突胶质细胞从髓鞘形成前向髓鞘形成表型的转变中起着至关重要的作用。在人脑中，我们发现MYRF在NogoA和CNP阳性少突胶质细胞中表达。在MS中，与髓鞘再生阴影斑块相比，在慢性脱髓鞘病变中少突胶质细胞谱系细胞和表达MYRF的NogoA+少突胶质细胞的密度和比例均较低。在脱髓鞘的MS病变中表达MYRF的少突胶质细胞谱系细胞的相对稀缺首次证明，慢性病变缺乏表达这种髓鞘再生所必需的转录因子的少突胶质细胞，并支持未能完全分化是髓鞘再生失败的基础的观点。
Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase pi positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure.