Human amniotic mesenchymal stem cell-derived exosome inhibits ferroptosis through the suppression of JNK/MAPK-mediated EGR1 expression in spontaneous intracerebral hemorrhage

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-09-17 DOI:10.1016/j.brainresbull.2025.111553

Yiheng Wang, Liangfu Zhou, Kan Xu

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引用次数: 0

Abstract

Introduction

Spontaneous intracerebral hemorrhage (ICH) represents an essential part of stroke, wherein ferroptosis is identified as a critical factor leading to the pathogenesis. Symptomatical treatments are mainly adopted which tend to leave severe neurological deficits. Recently, human amniotic mesenchymal stem cell (hAMSC) therapy has developed rapidly in the field of regenerative medicine, with its secreted exosomes (hAMSC-Exos) regarded as effective alternatives owing to the ability to penetrate the blood-brain barrier. Therefore, we aim to explore the therapeutic efficacy as well as molecular mechanism of hAMSC-Exos in ICH models.

Methods

Firstly, hAMSCs and their exosomes were extracted and characterized. Subsequently, the impact of hAMSC-Exos was assessed by evaluating the restoration of neurological function in ICH rat models induced by collagenase VII and in PC12 cells induced by hemin. Moreover, transcriptome sequencing of PC12 cell models identified the potential hub genes and pathways, which were subsequently verified through the western blot among the groups and further examined by the overexpression plasmid transfection and pathway activator treatment.

Results

hAMSC-Exos were successfully obtained and characterized. Afterwards, the in vivo and in vitro functional experiments demonstrated the effectiveness of hAMSC-Exos therapy in ICH models by reducing the level of ferroptosis, apoptosis and inflammatory factors and restoring the neurological function. Transcriptome sequencing identified the hub gene Egr1 and the key pathway MAPK, which were subsequently verified by the western blot. Specifically, hAMSC-Exos reduced the elevated EGR1 expression and p-JNK/JNK ratio in the ICH model. However, EGR1 overexpression plasmid transfection and anisomycin treatment reactivated ferroptosis in hAMSC-Exos-treated ICH models. Notably, the expression of EGR1 was increased following anisomycin administration.

Conclusion

The hAMSC-Exos may attenuate post-ICH ferroptosis and restore neurological function via down-regulating EGR1 mediated by JNK/MAPK in the rat and PC12 cell model of ICH, which might provide new approaches and drug targets in the management of the disease.

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人羊膜间充质干细胞衍生的外泌体通过抑制JNK/ mapk介导的EGR1在自发性脑出血中的表达来抑制铁凋亡。

自发性脑出血（自发性脑出血）是中风的重要组成部分，其中铁下垂被认为是导致其发病的关键因素。主要采用对症治疗，往往会留下严重的神经功能缺损。近年来，人羊膜间充质干细胞（hAMSC）治疗在再生医学领域发展迅速，其分泌外泌体（hAMSC- exos）因其能够穿透血脑屏障而被认为是有效的替代疗法。因此，我们旨在探讨hAMSC-Exos在ICH模型中的治疗效果及分子机制。方法：首先提取hAMSCs及其外泌体并进行表征。随后，通过评估胶原酶VII诱导的脑出血大鼠模型和hemin诱导的PC12细胞的神经功能恢复情况来评估hAMSC-Exos的影响。此外，PC12细胞模型的转录组测序鉴定了潜在的枢纽基因和通路，随后通过组间western blot验证，并通过过表达质粒转染和通路激活剂处理进一步检测。结果：成功获得了hAMSC-Exos并对其进行了表征。随后，在体内和体外功能实验中证实了hAMSC-Exos治疗ICH模型的有效性，可降低铁吊、细胞凋亡和炎症因子水平，恢复神经功能。转录组测序鉴定出枢纽基因Egr1和关键通路MAPK，随后通过western blot进行验证。具体来说，hAMSC-Exos降低了ICH模型中升高的EGR1表达和p-JNK/JNK比值。然而，在hamsc - exos处理的ICH模型中，EGR1过表达质粒转染和大霉素处理可重新激活铁下垂。值得注意的是，给药后EGR1的表达增加。结论：hAMSC-Exos可通过下调JNK/MAPK介导的EGR1在脑出血大鼠及脑出血PC12细胞模型中的表达，减轻脑出血后铁凋亡，恢复神经功能，可能为脑出血的治疗提供新的途径和药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.