[Effects and mechanisms of hpcMSC transplantation in ameliorating cognitive dysfunction, neuroinflammation, and hippocampal neuronal damage in stroke mice].

细胞与分子免疫学杂志 Pub Date : 2025-06-01
Guangping Hao, Shanyou Song, Mengjun Li
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引用次数: 0

Abstract

Objective To investigate the effects and underlying mechanisms of human placental chorionic plate-derived mesenchymal stem cells (hpcMSCs) on cognitive dysfunction, neuroinflammation, neuronal damage and synaptic plasticity in a mouse model of stroke. Methods A mouse model of middle cerebral artery occlusion (MCAO) was adopted. The mice were randomly divided into three groups: sham operation group, MCAO group and hpcMSCs treatment group, with seven mice in each group. The hpcMSCs treatment group received hpcMSCs transplantation on the 1st, 3rd and 10th day after MCAO. One month after MCAO, the cognitive ability of the mice was evaluated by Morris water maze and Y maze behavioral tests; the morphological changes and synaptic functions of hippocampal neurons were analyzed by HE staining, Nissl staining, Golgi staining and immunofluorescence staining techniques; the density and activation status of microglia was analyzed by Fluorescent labeling method; the levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in brain tissue were analyzed by ELISA; the expressions of phosphorylated-mitogen-activated protein kinase kinase 1 (p-MEK1), phosphorylated-extracellular regulated protein kinase (p-ERK) and phosphorylated-cAMP-response element binding protein (p-CREB) and other proteins related to neuroprotection in the signal pathways were detected by Western blotting; and electrophysiological detection was performed using hippocampal slices in vitro. Results Compared with the MCAO group, mice in the hpcMSCs treatment group showed significant improvements, including improved cognitive ability, alleviated neuroinflammation (demonstrated by reduced microglial activation and decreased levels of inflammatory factors TNF-α, IL-1β and IL-6), and increased neuronal density with normalized morphology of neurons in the hippocampal CA1 region. The treatment group also demonstrated a significantly increased number of Nissl-positive cells and density of dendritic spines of hippocampal neurons, along with restored frequency of miniature excitatory postsynaptic potential (mEPSP). Moreover, hpcMSCs treatment significantly increased the expression levels of p-MEK1, p-ERK and p-CREB in the hippocampus. Conclusion Transplantation of hpcMSCs ameliorates cognitive dysfunction and hippocampal neuronal injury in stroke mice through the reduction of neuroinflammation, restoration of hippocampal neuronal function, promotion of synaptic plasticity and activation of the MEK/ERK/CREB signaling pathway. These findings suggest a new potential therapeutic approach for post-stroke neural repair.

[hpcMSC移植改善脑卒中小鼠认知功能障碍、神经炎症和海马神经元损伤的作用和机制]。
目的探讨人胎盘绒毛膜板源间充质干细胞(hpcMSCs)对脑卒中小鼠模型认知功能障碍、神经炎症、神经元损伤和突触可塑性的影响及其机制。方法建立小鼠大脑中动脉闭塞(MCAO)模型。将小鼠随机分为假手术组、MCAO组和hpcMSCs治疗组,每组7只。hpcMSCs治疗组分别于MCAO后第1、3、10天进行hpcMSCs移植。MCAO 1个月后,采用Morris水迷宫和Y迷宫行为测试评价小鼠的认知能力;采用HE染色、尼氏染色、高尔基染色和免疫荧光染色技术分析海马神经元的形态变化和突触功能;荧光标记法分析小胶质细胞的密度和激活状态;ELISA法检测大鼠脑组织中肿瘤坏死因子α (TNF-α)、白细胞介素1β (IL-1β)、IL-6水平;Western blotting检测信号通路中磷酸化丝裂原活化蛋白激酶激酶1 (p-MEK1)、磷酸化细胞外调节蛋白激酶(p-ERK)和磷酸化camp反应元件结合蛋白(p-CREB)等神经保护相关蛋白的表达;并用离体海马切片进行电生理检测。结果与MCAO组相比,hpcMSCs治疗组小鼠表现出显著改善,包括认知能力提高,神经炎症减轻(表现为小胶质细胞活化减少,炎症因子TNF-α、IL-1β和IL-6水平降低),海马CA1区神经元形态正常化,神经元密度增加。治疗组海马神经元nissl阳性细胞数量和树突棘密度显著增加,微兴奋性突触后电位(mEPSP)频率恢复。此外,hpcMSCs处理显著增加了海马中p-MEK1、p-ERK和p-CREB的表达水平。结论hpcMSCs移植可减轻脑卒中小鼠的神经炎症,恢复海马神经元功能,促进突触可塑性,激活MEK/ERK/CREB信号通路,改善脑卒中小鼠的认知功能障碍和海马神经元损伤。这些发现为中风后神经修复提供了一种新的潜在治疗方法。
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