Polysialylation at Early Stages of Oligodendrocyte Differentiation Promotes Myelin Repair
Polysialylation at Early Stages of Oligodendrocyte Differentiation Promotes Myelin Repair
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DOI：
10.1523/jneurosci.1147-17.2017
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发表时间：
2017-08
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通讯作者：
Sebastian Werneburg;Hazel L S Fuchs;I. Albers;H. Burkhardt;V. Gudi;T. Skripuletz;M. Stangel;R. Gerardy-Schahn;H. Hildebrandt
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作者：
Sebastian Werneburg;Hazel L S Fuchs;I. Albers;H. Burkhardt;V. Gudi;T. Skripuletz;M. Stangel;R. Gerardy-Schahn;H. Hildebrandt
聚唾液酸是由聚唾液酸转移酶ST 8 SIA 2和ST 8 SIA 4产生的神经细胞粘附分子（NCAM）的聚糖修饰。在多发性硬化斑块中检测到聚唾液酸，但其在髓鞘再生中的有益或不利作用尚不清楚。在这里，我们表明，尽管发育迟缓，髓鞘形成在发病时和在cuprizone诱导脱髓鞘不受影响的雄性Ncam 1 −/−或St 8 sia 2 −/−小鼠。然而，髓鞘再生，少突胶质细胞密度的恢复，和运动恢复后，cuprizone治疗停止受到损害。NCAM-或ST 8 SIA 2-阴性少突胶质细胞前体的分化受损表明了潜在的细胞自主机制。相比之下，ST 8 SIA 4阴性培养物中的过早分化解释了先前在St 8 sia 4 −/−小鼠中观察到的加速髓鞘再生。人干细胞衍生的和原代鼠少突胶质细胞分化过程中的mRNA谱表明，ST 8 SIA 2和ST 8 SIA 4的相反作用源于顺序表达。我们还提供了证据表明，9-顺式维甲酸和人工聚唾液酸化的少突胶质细胞前体的细菌聚唾液酸转移酶的ST 8 SIA 2的增强机制，以促进少突胶质细胞分化。因此，聚唾液酸转移酶的差异靶向和聚唾液酸工程是推进脱髓鞘疾病治疗的有前景的策略。意义声明聚唾液酸（polySia）在髓鞘修复中的有益或不利作用是一个长期存在的问题。作为神经细胞粘附分子（NCAM）的修饰，polySia由聚唾液酸转移酶ST 8 SIA 2和ST 8 SIA 4产生。在这里，我们证明，NCAM和ST 8 SIA 2促进少突胶质细胞分化和髓鞘修复，以及铜蛋白诱导的脱髓鞘后的运动恢复。相反，ST 8 SIA 4延迟少突胶质细胞分化，解释了其在髓鞘再生中的不利作用。聚唾液酸转移酶的这些相反作用基于不同的表达谱。9-顺式维甲酸增强ST 8 SIA 2表达，为理解其如何支持少突胶质细胞分化和髓鞘再生提供了机制。此外，细胞表面的人工聚唾液酸化促进少突胶质细胞分化。因此，促进ST 8 SIA 2和polySia的工程化是改善髓鞘修复的有希望的策略。
Polysialic acid is a glycan modification of the neural cell adhesion molecule (NCAM) produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Polysialic acid has been detected in multiple sclerosis plaques, but its beneficial or adverse role in remyelination is elusive. Here, we show that, despite a developmental delay, myelination at the onset and during cuprizone-induced demyelination was unaffected in male Ncam1−/− or St8sia2−/− mice. However, remyelination, restoration of oligodendrocyte densities, and motor recovery after the cessation of cuprizone treatment were compromised. Impaired differentiation of NCAM- or ST8SIA2-negative oligodendrocyte precursors suggested an underlying cell-autonomous mechanism. In contrast, premature differentiation in ST8SIA4-negative cultures explained the accelerated remyelination previously observed in St8sia4−/− mice. mRNA profiling during differentiation of human stem cell-derived and primary murine oligodendrocytes indicated that the opposing roles of ST8SIA2 and ST8SIA4 arise from sequential expression. We also provide evidence that potentiation of ST8SIA2 by 9-cis-retinoic acid and artificial polysialylation of oligodendrocyte precursors by a bacterial polysialyltransferase are mechanisms to promote oligodendrocytic differentiation. Thus, differential targeting of polysialyltransferases and polysialic acid engineering are promising strategies to advance the treatment of demyelinating diseases. SIGNIFICANCE STATEMENT The beneficial or adverse role of polysialic acid (polySia) in myelin repair is a long-standing question. As a modification of the neural cell adhesion molecule (NCAM), polySia is produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Here we demonstrate that NCAM and ST8SIA2 promote oligodendrocyte differentiation and myelin repair as well as motor recovery after cuprizone-induced demyelination. In contrast, ST8SIA4 delays oligodendrocyte differentiation, explaining its adverse role in remyelination. These opposing roles of the polysialyltransferases are based on different expression profiles. 9-cis-retinoic acid enhances ST8SIA2 expression, providing a mechanism for understanding how it supports oligodendrocyte differentiation and remyelination. Furthermore, artificial polysialylation of the cell surface promotes oligodendrocyte differentiation. Thus, boosting ST8SIA2 and engineering of polySia are promising strategies for improving myelin repair.