The combination of human umbilical cord-derived and their led to significant improvements in multiple behavioral and biological aspects in a mouse model of .
Both individual treatments of human umbilical cord-derived mesenchymal stem cells and extracellular vesicles showed limited efficacy in alleviating Autism Spectrum Disorder-like symptoms.
The combined therapy resulted in notable enhancements in social interaction and a reduction in repetitive behaviors.
This combination therapy normalized levels of neuroinflammatory cytokines and oxidative stress in the brain.
Improvements were observed in the synaptic and mitochondrial structure in critical brain regions.
The treatment also contributed to gut microbiota balance by increasing beneficial bacteria like Lactobacillus and decreasing harmful pathogens.
Simplified
INTRODUCTION: (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Accumulating evidence implicates neuroimmune dysregulation and gut microbiota dysbiosis in its pathogenesis, yet effective therapies targeting these mechanisms are lacking. This study investigated the therapeutic efficacy of human umbilical cord-derived (hUCMSCs) and their (EVs), both alone and in combination, in a valproic acid (VPA)-induced ASD mouse model.
METHODS: VPA-exposed C57BL/6 mice were randomized into five groups: control, VPA, hUCMSCs alone, EVs alone, and hUCMSCs + EVs combination. Behavioral tests, biochemical analyses, 16 S rRNA sequencing, immunofluorescence, and transmission electron microscopy (TEM) were performed RESULTS: While both hUCMSCs and EVs alone showed some beneficial effects on certain ASD-like symptoms, each exhibited limited efficacy in achieving comprehensive remediation. In contrast, the combined hUCMSCs + EVs therapy yielded the most robust improvements across multiple domains, including social interaction and repetitive behaviors. Furthermore, the combination therapy synergistically normalized neuroinflammatory cytokine levels and oxidative stress, restored synaptic and mitochondrial ultrastructure in key brain regions, and promoted gut microbiota homeostasis by enriching beneficial bacteria such as Lactobacillus and reducing pathogens.
DISCUSSION: These results highlight that although individual treatments offer partial relief, only the combined strategy fully restores neuroimmune-microbiota homeostasis, demonstrating a complementary and synergistic therapeutic effect. This study establishes a novel dual-target approach leveraging systemic hUCMSCs and CNS-targeted EVs, providing a promising translational strategy for ASD through orchestrated regulation of the neuro-immune-microbiota axis.
Key numbers
< 0.0001
Increase in Social Interaction Time
Comparison of treatment effects on social interaction in VPA-exposed mice.
< 0.0001
Decrease in Repetitive Behaviors
Behavioral analysis of marble-burying test results in treated vs. VPA-exposed mice.
< 0.0001
Normalization of IL-1β Levels
Comparison of IL-1β levels in the prefrontal cortex of treated vs. VPA-exposed mice.
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Declarations. Ethics approval and consent to participate: (1) Animal ethics declaration:All animal experiments were conducted in compliance with the ARRIVE guidelines and approved by the Institutional Animal Care and Use Committee (IACUC) of [Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences] for the project ' Establishment of autism models in SD rats and C57 mice and stem cell therapy ' (IACUC: No. 2023081). Final approval was granted on [November 20, 2023]. (2) Statement of life sciences and medical ethics: Human sample collection was approved by the [Ethics Committee of Hunan Provincial Maternal and Child Health Hospital] (Approval No. 202120) for the project [Preclinical Research on Stem Cell Therapy for Diabetes in Children] on [27 April 2021]. Written informed consent was obtained from all participants/guardians. All procedures followed the guidelines of the National Health and Medical Research Council of China and received approval(GIBH-LMEC2024-091-01(AL)) from the Committee on Life Sciences and Medical Ethics of Guangzhou Institutes of Biomedicine and Health, CAS for the project [Research on the Mechanism of stem Cell Therapy in the mouse Autism Model Induced by VPA] on [August 15, 2024]. Competing interests: The authors declare no competing interests.
