In the peripheral nervous system (PNS), proper development of Schwann cells (SCs) contributing to axonal myelination is critical for neuronal function. Impairments of SCs or neuronal axons give rise to several myelin‐related disorders, including dysmyelinating and demyelinating diseases. Pathological mechanisms, however, have been understood at the elementary level and targeted therapeutics has remained undeveloped. Here, we identify Fibulin 5 (FBLN5), an extracellular matrix (ECM) protein, as a key paracrine factor of human Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs) to control the development of SCs. We show that co‐culture with WJ‐MSCs or treatment of recombinant FBLN5 promotes the proliferation of SCs through ERK activation, whereas FBLN5‐depleted WJ‐MSCs do not. We further reveal that during myelination of SCs, FBLN5 binds to Integrin and modulates actin remodeling, such as the formation of lamellipodia and filopodia, through RAC1 activity. Finally, we show that FBLN5 effectively restores the myelination defects of SCs in the zebrafish model of Charcot‐Marie‐Tooth (CMT) type 1, a representative demyelinating disease. Overall, our data propose human WJ‐MSCs or FBLN5 protein as a potential treatment for myelin‐related diseases, including CMT.

中文翻译：

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沃顿氏胶质间充质干细胞分泌的旁分泌因子5球蛋白通过整合素RAC1信号轴减轻周围神经系统的髓鞘缺损

在周围神经系统（PNS）中，促成轴突髓鞘形成的雪旺细胞（SCs）的正常发育对于神经元功能至关重要。SC或神经元轴突的损伤会导致多种髓鞘相关疾病，包括髓鞘异常和脱髓鞘疾病。然而，在基本水平上已经了解了病理机制，并且尚未开发出靶向疗法。在这里，我们确定纤维蛋白5（FBLN5）是一种细胞外基质（ECM）蛋白，它是沃顿商学院的果冻间充质干细胞（WJ-MSC）来控制SC发育的关键旁分泌因子。我们显示与WJ‐MSC的共培养或重组FBLN5的处理可通过ERK激活促进SC的增殖，而FBLN5耗尽的WJ‐MSC则没有。我们进一步揭示，在SC的髓鞘形成过程中，FBLN5通过RAC1活性与整联蛋白结合并调节肌动蛋白重塑，例如形成片状脂质体和丝状伪足。最后，我们证明，FBLN5在Charcot-Marie-Tooth（CMT）1型斑马鱼模型（一种典型的脱髓鞘疾病）中可有效恢复SC的髓鞘缺损。总体而言，我们的数据表明，人类WJ-MSC或FBLN5蛋白可作为治疗髓鞘相关疾病（包括CMT）的潜在方法。