Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, 218#Ji Xi Road, Hefei, 230032, Anhui, China.
Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, 218#Ji Xi Road, Hefei, 230032, Anhui, China.
Biomed Pharmacother. 2021 Feb;134:111168. doi: 10.1016/j.biopha.2020.111168. Epub 2021 Jan 1.
Axonal demyelination is a consistent pathological characteristic of Spinal cord injury (SCI). Promoting differentiation of oligodendrocytes is of importance for remyelination. Conversion of reactive astrocytes with stem cell potential to oligodendrocytes is proposed as an innovative strategy for SCI repair. Neuregulin-1 (Nrg1) plays an essential role in the differentiation of oligodendrocytes. Therefore, it's a potential treatment for demyelination in SCI that using Nrg1 to drive reactive astrocytes toward oligodendrocyte lineage cells. In this study, tumor necrosis factor-α (TNF-α) was used to induce dedifferentiation of primary rat spinal cord astrocytes into reactive astrocytes and Nrg1 was used to induce astrocytes in vitro and in vivo. The results showed that astrocytes treated with TNF-α expressed immaturity markers CD44 and Musashi1 at mRNA and protein levels, indicating that TNF-α induced the stem cell state of astrocytes. Nrg1 induced reactive astrocytes to express oligodendrocyte markers PDGFR-α and O4 at mRNA and protein levels, indicating that Nrg1 directly converts reactive astrocytes toward oligodendrocyte lineage cells. Moreover, upregulation of PI3K-AKT-mTOR signaling activation in response to Nrg1 was observed. In rats with SCI, intrathecal treatment with Nrg1 converted reactive astrocytes to oligodendrocyte lineage cells, inhibited astrogliosis, promoted remyelination, protected axons and eventually improved BBB score. All the biological effects of Nrg1 were significantly reversed by the co-administration of Nrg1 and ErbB inhibitor, suggesting that Nrg1 functioned through the receptor ErbB. Our findings indicate that Nrg1 is sufficient to trans-differentiate reactive astrocytes to oligodendrocytes via the PI3K-AKT-mTOR signaling pathway and repair SCI. Delivery of Nrg1 for the remyelination processes could be a promising strategy for spinal cord repair.
轴突脱髓鞘是脊髓损伤 (SCI) 的一种一致的病理特征。促进少突胶质细胞分化对于髓鞘修复很重要。将具有干细胞潜能的反应性星形胶质细胞转化为少突胶质细胞被提出作为 SCI 修复的一种创新策略。神经调节蛋白 1 (Nrg1) 在少突胶质细胞的分化中起着至关重要的作用。因此，使用 Nrg1 驱动反应性星形胶质细胞向少突胶质细胞谱系细胞分化，是治疗 SCI 脱髓鞘的一种潜在方法。在这项研究中，肿瘤坏死因子-α (TNF-α) 被用于诱导原代大鼠脊髓星形胶质细胞去分化为反应性星形胶质细胞，Nrg1 被用于体外和体内诱导星形胶质细胞。结果表明，TNF-α 处理的星形胶质细胞在 mRNA 和蛋白质水平上表达不成熟标志物 CD44 和 Musashi1，表明 TNF-α诱导了星形胶质细胞的干细胞状态。Nrg1 诱导反应性星形胶质细胞在 mRNA 和蛋白质水平上表达少突胶质细胞标志物 PDGFR-α 和 O4，表明 Nrg1 直接将反应性星形胶质细胞转化为少突胶质细胞谱系细胞。此外，观察到 Nrg1 诱导反应性星形胶质细胞中 PI3K-AKT-mTOR 信号通路的激活上调。在 SCI 大鼠中，鞘内给予 Nrg1 将反应性星形胶质细胞转化为少突胶质细胞谱系细胞，抑制星形胶质细胞增生，促进髓鞘再生，保护轴突，最终改善 BBB 评分。Nrg1 与 ErbB 抑制剂共同给药显著逆转了 Nrg1 的所有生物学效应，表明 Nrg1 通过受体 ErbB 发挥作用。我们的研究结果表明，Nrg1 通过 PI3K-AKT-mTOR 信号通路足以将反应性星形胶质细胞转化为少突胶质细胞，并修复 SCI。Nrg1 用于髓鞘形成过程的递送可能是脊髓修复的一种有前途的策略。
