Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries.
Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries.
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DOI：
10.1016/j.apsb.2022.06.007
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发表时间：
2023-05
影响因子：
14.5
通讯作者：
Cui, Wenguo
中科院分区：
文献类型：
--
作者：
Ruan, Huitong;Li, Yongfang;Wang, Cheng;Jiang, Yixu;Han, Yulong;Li, Yiwei;Zheng, Dandan;Ye, Jing;Chen, Gang;Yang, Guo-yuan;Deng, Lianfu;Guo, Ming;Zhang, Xingcai;Tang, Yaohui;Cui, Wenguo
关键词：
中枢神经系统（CNS）损伤，包括中风、创伤性脑损伤和脊髓损伤，是死亡和长期残疾的重要原因，并且难以治愈，主要是由于有限的神经元再生和胶质瘢痕形成。在此，我们应用由M2小胶质细胞分泌的细胞外囊泡（EV）来促进损伤部位的神经干细胞（NSC）的分化，同时通过无铜点击化学在其表面用损伤血管靶向肽（DA 7 R）和干细胞募集因子（SDF-1）修饰它们以募集NSC，诱导其神经元分化，并在损伤部位充当纳米载体（Dual-EV）。结果表明，Dual-EV能靶向人脐静脉内皮细胞（HUVECs），募集神经干细胞，促进神经干细胞向神经元分化。此外，通过生物信息学分析发现，与Dual-M0-EV相比，10种miRNA在Dual-M2-EV中上调，并且通过流式细胞术进一步进行的NSC分化实验揭示，在这些miRNA中，miR-30 b-3 p、miR-222- 3 p、miR-129- 5 p和miR-155- 5 p可能发挥诱导NSC分化为神经元的作用。体内实验表明，Dual-EV纳米载体在中风模型小鼠的缺血区域中实现了改善的积累，增强了NSC募集，并增加了神经发生。这项工作为治疗CNS损伤后的神经元再生以及内源性干细胞提供了新的见解，并为改善人类健康提供了点击化学EV/肽/趋化因子和相关纳米载体。点击化学细胞外囊泡/肽/趋化因子纳米微粒通过靶向血管、募集神经干细胞（NSC）并诱导其分化为神经元来修复中枢神经系统（CNS）损伤。
Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health. Click chemistry extracellular vesicle/peptide/chemokine nanomissiles repair central nervous systems (CNS) injuries by targeting blood vessels, recruiting neural stem cells (NSCs) and inducing their differentiation into neurons.
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