3KO-NSCs ameliorate behavioral deficits and modulate gut microbiota in a VPA-induced C57BL/6 mouse model of autism.

IF 5.9 2区医学 Q1 IMMUNOLOGY

Frontiers in Immunology Pub Date : 2025-10-02 eCollection Date: 2025-01-01 DOI:10.3389/fimmu.2025.1680179

Caixia Wu, Xianjie Li, Han Wang, Xiaoya Yang, Zhaoming Liu

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引用次数: 0

Abstract

Background: Autism spectrum disorder (ASD) involves complex neurological and gastrointestinal pathophysiology. Existing therapies rarely address the gut-brain axis connection. This study evaluated the therapeutic potential of immune-evasive human induced pluripotent stem cell-derived neural stem cells (3KO-NSCs) in a mouse model of ASD.

Methods: We used a valproic acid (VPA)-induced ASD model in C57BL/6 mice. Mice received systemic administration of 3KO-NSCs. Assessments included behavioral assays (social interaction, repetitive behaviors), hippocampal cytokine profiling (IL-6, TNF-α), 16S rRNA sequencing for gut microbiota analysis, immunohistochemistry (Iba1⁺ microglia), and ultrastructural synaptic analysis.

Results: 3KO-hiPSC-NSC treatment significantly ameliorated VPA-induced ASD-like behaviors. It reduced hippocampal neuroinflammation (decreased IL-6 and TNF-α) and attenuated microglial overactivation (reduced Iba1+ cells), correcting synaptic pruning abnormalities. Concurrently, treatment restored gut microbiota diversity (increased Shannon index), enriching Bacteroides and reducing pro-inflammatory Proteobacteria.

Conclusions: 3KO-NSCs exert dual therapeutic effects by mitigating central neuroinflammation and rebalancing gut microbiota. This provides the first direct evidence that stem cell therapy can modulate the gut-brain axis to treat ASD, positioning 3KO-NSCs as a novel bifunctional therapeutic strategy.

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在vpa诱导的C57BL/6自闭症小鼠模型中，3KO-NSCs改善了行为缺陷并调节了肠道微生物群。

背景：自闭症谱系障碍（ASD）涉及复杂的神经和胃肠病理生理。现有的治疗方法很少涉及肠-脑轴连接。本研究评估了免疫逃避人诱导多能干细胞来源的神经干细胞（3KO-NSCs）在ASD小鼠模型中的治疗潜力。方法：采用丙戊酸（VPA）诱导的C57BL/6小鼠ASD模型。小鼠全身给予3KO-NSCs。评估包括行为分析（社会互动，重复行为），海马细胞因子分析（IL-6, TNF-α）， 16S rRNA测序用于肠道微生物群分析，免疫组织化学（Iba1+小胶质细胞）和超微结构突触分析。结果：3KO-hiPSC-NSC治疗显著改善vpa诱导的asd样行为。它可以减轻海马神经炎症（降低IL-6和TNF-α）和减轻小胶质细胞过度激活（减少Iba1+细胞），纠正突触修剪异常。同时，治疗恢复了肠道微生物群的多样性（增加了香农指数），丰富了拟杆菌，减少了促炎变形杆菌。结论：3KO-NSCs具有减轻中枢神经炎症和平衡肠道菌群的双重治疗作用。这提供了干细胞治疗可以调节肠-脑轴治疗ASD的第一个直接证据，将3KO-NSCs定位为一种新的双功能治疗策略。

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

Frontiers in Immunology IMMUNOLOGY-

CiteScore

9.80

自引率

11.00%

发文量

7153

审稿时长

14 weeks

期刊介绍： Frontiers in Immunology is a leading journal in its field, publishing rigorously peer-reviewed research across basic, translational and clinical immunology. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Immunology is the official Journal of the International Union of Immunological Societies (IUIS). Encompassing the entire field of Immunology, this journal welcomes papers that investigate basic mechanisms of immune system development and function, with a particular emphasis given to the description of the clinical and immunological phenotype of human immune disorders, and on the definition of their molecular basis.