Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys.
Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys.
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DOI：
10.1186/s12974-023-02880-0
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发表时间：
2023-09-02
影响因子：
9.3
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中科院分区：
文献类型：
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了解灵长类大脑中的小胶质神经免疫相互作用对于开发皮层损伤（如中风或创伤性脑损伤）的治疗方法至关重要。我们之前的研究表明，间充质来源的细胞外囊泡（msc - ev）通过促进稳态分支小胶质细胞，减少损伤相关神经元的高兴奋性，增强皮层周围皮层的突触可塑性，从而增强初级运动皮层（M1）损伤后的老年猕猴的运动恢复。老龄雌性恒河猴在损伤后24小时和14天分别静脉输注载药（veh）或ev，通过手术切除M1手部皮层表面层的头部血管，引起局灶性病变。目前的研究使用相同的队列来解决这些损伤和恢复相关的变化如何与小胶质细胞和神经元突触之间的结构和分子相互作用相关。通过多标记免疫组织化学、高分辨率显微镜和基因表达分析，我们量化了突触标记物（VGLUTs、GLURs、VGAT、gabar）、小胶质细胞标记物（Iba1、P2RY12）和C1q（一种用于小胶质细胞介导的突触吞噬的补体通路蛋白）在淋巴结周围M1和运动前皮层（PMC）中的共表达。我们将该病变组与年龄匹配的非病变对照组（ctr）进行比较。我们的研究结果揭示了病变相关的病变周围兴奋性突触的丧失，这种情况通过EV治疗得到改善。此外，我们发现ev对小胶质细胞和C1q表达的区域依赖性作用。在病灶周围M1中，EV治疗和增强的功能恢复与C1q +肥厚性小胶质细胞的表达增加有关，C1q +肥厚性小胶质细胞被认为在碎片清除和抗炎功能中起作用。在PMC中，EV治疗与C1q +突触标记和小胶质-脊柱接触减少有关。我们的研究结果表明，EV治疗可能通过清除病灶周围M1的急性损伤来增强突触可塑性，从而防止PMC的慢性炎症和过度突触丢失。这些机制可能保护突触皮质运动网络和平衡的规范M1/PMC突触功能，以支持损伤后的功能恢复。在线版本包含补充材料，可在10.1186/s12974-023-02880-0获得。
Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia–spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury. The online version contains supplementary material available at 10.1186/s12974-023-02880-0.
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影响因子：
4.7
作者：
Barko, Kelly;Shelton, Micah;Xue, Xiangning;Afriyie-Agyemang, Yvette;Puig, Stephanie;Freyberg, Zachary;Tseng, George C.;Logan, Ryan W.;Seney, Marianne L.
通讯作者：
Seney, Marianne L.
影响因子：
7.9
作者：
Bottenfield KR;Bowley BGE;Pessina MA;Medalla M;Rosene DL;Moore TL
通讯作者：
Moore TL
影响因子：
1.5
作者：
Calderazzo, Samantha;Covert, Margaret;De Alba, Diego;Bowley, Bethany E.;Pessina, Monica A.;Rosene, Douglas L.;Buller, Benjamin;Medalla, Maria;Moore, Tara L.
通讯作者：
Moore, Tara L.
影响因子：
6.1
作者：
Benowitz LI;Carmichael ST
通讯作者：
Carmichael ST
影响因子：
34.7
作者：
Brown, Guy C.;Neher, Jonas J.
通讯作者：
Neher, Jonas J.