The participation of microglia in CNS development and homeostasis indicate that these cells are pivotal for the regeneration that occurs after demyelination. The clearance of myelin debris and the inflammatory-dependent activation of local oligodendrocyte progenitor cells in a demyelinated lesion is dependent on the activation of M2c microglia, which display both phagocytic and healing functions. Emerging interest has been raised about the role of Wnt/β-catenin signaling in oligodendrogenesis and myelination. Besides, cytokines and growth factors released by microglia can control the survival, proliferation, migration, and differentiation of neural stem cells (NSCs), contributing to remyelination through the oligodendrocyte specification of this adult neurogenic niche. TMEV-IDD model was used to study the contribution of dorsal SVZ stem cells to newly born oligodendrocytes in the corpus callosum following demyelination by (i) en-face dorsal SVZ preparations; (ii) immunohistochemistry; and (iii) cellular tracking. By RT-PCR, we analyzed the expression of Wnt proteins in demyelinated and remyelinating corpus callosum. Using in vitro approaches with microglia cultures and embryonic NSCs, we studied the role of purified myelin, Wnt proteins, and polarized microglia-conditioned medium to NSC proliferation and differentiation. One-way ANOVA followed by Bonferroni’s post-hoc test, or a Student’s t test were used to establish statistical significance. The demyelination caused by TMEV infection is paralleled by an increase in B1 cells and pinwheels in the dorsal SVZ, resulting in the mobilization of SVZ proliferative progenitors and their differentiation into mature oligodendrocytes. Demyelination decreased the gene expression of Wnt5a and Wnt7a, which was restored during remyelination. In vitro approaches show that Wnt3a enhances NSC proliferation, while Wnt7a and myelin debris promotes oligodendrogenesis from NSCs. As phagocytic M2c microglia secrete Wnt 7a, their conditioned media was found to induce Wnt/β-Catenin signaling in NSCs promoting an oligodendroglial fate. We define here the contribution of microglia to Wnt production depending on their activation state, with M1 microglia secreting the Wnt5a protein and M2c microglia secreting Wnt7a. Collectively, our data reveal the role of reparative microglia in NSC oligodendrogenesis with the involvement of Wnt7a.

中文翻译：

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Wnt7a参与M2c小胶质细胞在神经干细胞少突胶质形成中的作用

小胶质细胞参与中枢神经系统发育和体内平衡表明，这些细胞对于脱髓鞘后发生的再生至关重要。髓鞘碎片的清除和脱髓鞘病灶中局部少突胶质细胞祖细胞的炎性依赖性激活取决于M2c小胶质细胞的激活，M2c小胶质细胞具有吞噬和愈合功能。关于Wnt /β-连环蛋白信号转导在少突胶质生成和髓鞘形成中的作用已经引起了越来越多的关注。此外，小胶质细胞释放的细胞因子和生长因子可以控制神经干细胞（NSC）的存活，增殖，迁移和分化，从而通过该成年神经源性利基的少突胶质细胞规格促进髓鞘再生。TMEV-IDD模型用于研究脱髓鞘后，背侧SVZ干细胞对call体中新生少突胶质细胞的贡献，方法是：（i）面对背侧SVZ制剂；（ii）免疫组织化学；（iii）细胞追踪。通过RT-PCR，我们分析了Wnt蛋白在脱髓鞘和重新髓鞘的call体中的表达。使用具有小胶质细胞培养物和胚胎NSC的体外方法，我们研究了纯化的髓磷脂，Wnt蛋白和极化的小胶质细胞条件培养基对NSC增殖和分化的作用。采用单向方差分析，Bonferroni事后检验或学生t检验来建立统计学显着性。由TMEV感染引起的脱髓鞘与背侧SVZ中B1细胞和风车的增加同时发生，导致SVZ增殖祖细胞的动员并将其分化为成熟的少突胶质细胞。脱髓鞘作用降低了Wnt5a和Wnt7a的基因表达，这在髓鞘再生期间得以恢复。体外方法显示，Wnt3a增强了NSC的增殖，而Wnt7a和髓磷脂碎片则促进了NSC的少突胶质生成。由于吞噬细胞的M2c小胶质细胞分泌Wnt 7a，因此发现它们的条件培养基在促进少突胶质细胞命运的NSC中诱导Wnt /β-Catenin信号传导。我们在这里定义小胶质细胞对Wnt产生的贡献，取决于它们的激活状态，其中M1小胶质细胞分泌Wnt5a蛋白，M2c小胶质细胞分泌Wnt7a。总的来说，我们的数据揭示了在Wnt7a参与下修复性小胶质细胞在NSC少突胶质生成中的作用。