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 π 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.

尽管大多数病变中都存在少突胶质前体细胞（OPC），但在大多数多发性硬化症（MS）病变中，髓鞘再生受限。该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的分化需要复杂的转录调控，这可能会在慢性MS病变中被破坏。在髓鞘再生病变和难于髓鞘再生的病变之间比较了几种转录因子的表达。特别地，少突胶质细胞转录因子髓磷脂调节因子（MYRF）对于发育过程中的髓鞘形成至关重要，但是其在髓鞘再生和MS病变表达中的作用尚不清楚。要了解MYRF在髓鞘再生中的作用，我们通过溶血卵磷脂诱导小鼠的call体脱髓鞘后，对命运的OPC进行了遗传定位，并确定MYRF在新的少突胶质细胞中表达。特定于OPCMyrf缺失并没有改变脱髓鞘后这些细胞的募集或增殖，但是降低了新的谷胱甘肽S-转移酶π阳性少突胶质细胞的密度。从OPC中删除Myrf后，脊髓和call体的后续髓鞘再生都受到严重损害。响应脱髓鞘作用而产生的单个OPC来源的少突胶质细胞在Myrf后显示出表达髓磷脂蛋白的能力很小删除。总的来说，这些数据证明了MYRF在髓鞘再生过程中在少突胶质细胞从前髓鞘表型转变为髓鞘表型中的关键作用。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，与脱髓鞘的阴影斑块相比，在慢性脱髓鞘的病变中表达MYRF的少突胶质细胞谱系细胞和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表明，慢性病变缺少少突胶质细胞，该少突胶质细胞表达该必需的转录因子用于髓鞘再生，并支持不能完全分化的基础是髓鞘再生失败的基础。