Depletion of SASH1, an astrocyte differentiation-related gene, contributes to functional recovery in spinal cord injury.
Depletion of SASH1, an astrocyte differentiation-related gene, contributes to functional recovery in spinal cord injury.
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DOI：
10.1111/cns.13998
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发表时间：
2023-01
影响因子：
5.5
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中科院分区：
文献类型：
--
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本研究旨在评估 SAM 和 SH3 结构域蛋白 1 (SASH1) 的缺失对脊髓损伤 (SCI) 后功能恢复的影响，并探讨星形胶质细胞中 SASH1 敲低促进轴突生长的可能机制。建立成年大鼠SCI模型。使用SASH1小干扰RNA（siSASH1）来研究其功能。通过 Basso-Bresnahan-Beattie (BBB) 测定评估后肢运动功能。通过qRT-PCR、Western blotting、ELISA和免疫组化方法评估基因表达。 SASH1 敲低改善了 SCI 后的 BBB 评分，并显着降低了 GFAP 表达。在培养的脊髓星形胶质细胞中，siSASH1 治疗减少了干扰素 γ 的释放，并增加了脑源性神经营养因子 (BDNF) 的释放。当与 SASH1 敲低的星形胶质细胞共培养时，轴突生长增加。神经元原肌球蛋白受体激酶 B（BDNF 受体）表达增加，尤其是在轴突尖端。当 NSC 分化为神经胶质细胞而不是神经元时，SASH1 表达增加。 SASH1 耗尽后，分化的 NSC 保持较高水平的巢蛋白和 BDNF 释放的增加。这些结果表明，SASH1 作为星形胶质细胞分化维持蛋白，SASH1 下调限制了神经胶质细胞的激活，有助于 SCI 后的功能恢复。在 NSC 分化为神经胶质细胞和脊髓损伤 (SCI) 过程中，SASH1 表达显着增加。原代星形胶质细胞中 SASH1 敲低增加了 BDNF 的释放并促进轴突生长； SASH1 敲低显着减少了星形胶质细胞的激活并改善了 SCI 后功能的恢复。
This study aimed to evaluate the effects of the depletion of SAM and SH3 domain‐containing protein 1 (SASH1) on functional recovery after spinal cord injury (SCI) and to investigate the possible mechanism of SASH1 knockdown in astrocytes facilitating axonal growth. SCI model was established in adult rats. SASH1 small interfering RNA (siSASH1) was used to investigate its function. Hindlimb motor function was evaluated by the Basso‐Bresnahan‐Beattie (BBB) assay. The gene expressions were evaluated by the methods of qRT‐PCR, Western‐blotting, ELISA, and immunohistochemistry. SASH1 knockdown improved the BBB scores after SCI and significantly reduced GFAP expression. In cultured spinal astrocytes, siSASH1 treatment decreased interferon‐γ release and increased brain‐derived neurotrophic factor (BDNF) release. When cocultured with SASH1‐knockdown astrocytes, axonal growth increased. The neuronal tropomyosin receptor kinase B (BDNF receptor) expression increased, especially in the axonal tips. SASH1 expression increased while NSCs differentiated into glial cells, instead of neurons. After SASH1 depletion, differentiated NSCs maintained a higher level of Nestin protein and an increase in BDNF release. These results indicate that SASH1 acts as an astrocytic differentiation‐maintaining protein, and SASH1 downregulation limits glial activation and contributes toward functional recovery after SCI. SASH1 expression increased significantly during NSCs differentiation into glial cells and spinal cord injury (SCI). SASH1 knockdown in primary astrocytes increased the release of BDNF and promoted axonal growth; SASH1 knockdown significantly reduced astrocytes activation and improved the recovery of function after SCI.
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影响因子：
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作者：
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通讯作者：
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