Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPsigma/alpha-actinin4 signaling pathway
Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPsigma/alpha-actinin4 signaling pathway
复制标题
硫酸软骨素蛋白多糖通过 PTPsigma/α-actinin4 信号通路抑制神经干/祖细胞迁移
DOI：
10.1002/jcb.28379
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发表时间：
2019
影响因子：
4
通讯作者：
Feng H.
中科院分区：
文献类型：
--
作者：
Zhong J;Lan C;Zhang C;Yang Y;Chen W. X;Zhang K. Y;Zhao H. L;Fang X. Y;Li H. H;Tan L;Wang P;Ge H. F;Hu R;Feng H.
神经干/祖细胞（NSPCs）是中枢神经系统（CNS）损伤后细胞替代治疗的一个有希望的候选细胞。然而，由于局部环境稳态紊乱，中枢神经系统损伤后，缺乏足够的NSPCs迁移和整合是基于细胞的治疗的一个重要挑战。中枢神经系统损伤后，硫酸软骨素蛋白多糖（CSPG）在病变处明显积累，破坏局部稳态。已有研究表明，CSPG是抑制中枢神经系统损伤后新生神经元轴突再生的主要成分。NSPCs是一种特殊的神经亚型，具有引导过程形成的能力来调节NSPCs的迁移，其机制与轴突再生相同。因此，CSPG对NSPCs迁移的影响及其潜在机制值得深入研究。本研究采用不同浓度的CSPG来评价其对NSPCs迁移的影响。结果表明，CSPG在24小时后以剂量依赖性的方式抑制NSPCs的迁移，从10µg/mL到80µg/mL。同时，进行了transwell分析来验证上述结果。我们的数据表明，免疫荧光染色显示，40µg/mL CSPG通过减少丝状足形成明显抑制NSPCs迁移。免疫荧光、逆转录聚合酶链反应和Western blot检测结果显示，40µg/mL CSPG可上调蛋白酪氨酸磷酸酶受体σ (PTPσ)的表达，降低α‐actiin4 （ACTN4）的表达。而使用PTPσ‐特异性小干扰RNA可减弱其抑制作用。此外，数据显示，40µg/mL CSPG促进NSPCs向胶质纤维酸性蛋白阳性细胞分化，并抑制NSPCs向MAP2和MBP阳性细胞分化。综上所述，这些数据表明CSPG通过PTPσ/ACTN4信号通路抑制NSPCs的迁移。与此同时,CSPG
Neural stem/progenitor cells (NSPCs) are a promising candidate for the cell‐replacement therapy after central nervous system (CNS) injury. However, the short of sufficient NSPCs migration and integration into the lesions is an essential challenge for cell‐based therapy after CNS injury due to the disturbance of local environmental homeostasis. Chondroitin sulfate proteoglycan (CSPG) is obviously accumulated at the lesions and destroyed local homeostasis after CNS injury. The previous study has demonstrated that the CSPG is a dominating ingredient inhibiting axonal regrowth of newly born neurons after CNS injury. NSPCs, a strain of special neural subtypes, hold the capacity of leading processes formation to regulate NSPCs migration, which has the same mechanism as axonal regrowth. Hence, it is worth investigating the effect of CSPG on NSPCs migration and its underlying mechanism. Here, different concentration of CSPG was used to evaluate its effect on NSPCs migration. The results showed that the CSPG suppressed NSPCs migration in a dose‐dependent manner from 10 to 80µg/mL with phase‐contrast microscopy after 24 hours. Meanwhile, transwell assays were performed to certify the above results. Our data indicated that the 40µg/mL CSPG obviously suppressed NSPCs migration via decreasing filopodia formation using immunofluorescence staining. Furthermore, data indicated that the 40 µg/mL CSPG upregulated protein tyrosine phosphatase receptor σ (PTPσ) expression and decreased α‐actinin4 (ACTN4) expression through immunofluorescence, reverse transcription polymerase chain reaction, and Western blot assays. While the inhibitory effect was attenuated using PTPσ‐specific small interfering RNA. In addition, data demonstrated that the 40µg/mL CSPG facilitated NSPCs differentiation into glial fibrillary acidic protein‐positive cells and inhibited NSPCs directing into MAP2‐and MBP‐positive cells. Collectively, these data demonstrated that the CSPG suppressed NSPCs migration through PTPσ/ACTN4 signaling pathway. Meanwhile, CSPG