Human Umbilical Cord Blood Mesenchymal Stem Cells Ameliorate Autism-Like Behaviors in a Valproic Acid-Induced Mouse Model via the IGF-1/Akt Signaling Pathway.

BACKGROUND

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that significantly impacts children's physical and mental health, yet effective pharmacological treatments remain limited. The primary objective of this study was to investigate the therapeutic effects of human umbilical cord blood mesenchymal stem cells (hUC-MSCs) on ASD, evaluate the safety profile of hUC-MSCs, and elucidate their underlying mechanisms and functional roles.

METHODS

In this study, we utilized the offspring of pregnant mice exposed to valproic acid (VPA) as an animal model of ASD. At the beginning of 5 weeks of age, 5 × 105 hUC-MSCs were administered into the lateral ventricles to evaluate their safety profile and elucidate their potential roles and underlying mechanisms. Specifically, we first monitored the growth and overall health status of the mice following hUC-MSC treatment and assessed potential toxic effects by performing H&E staining on major organs. Second, behavioral analyses were conducted to examine changes in social interaction, repetitive and stereotyped behaviors, and anxiety-like behaviors in young mice before and after hUC-MSC intervention. Finally, the mechanisms underlying the therapeutic effects of hUC-MSCs in ASD were explored using techniques such as RT-PCR, Western blot analysis, brain tissue staining, and neuron culture experiments.

RESULTS

Here, we demonstrate that hUC-MSCs effectively mitigate behavioral abnormalities in a VPA-induced mouse model of autism without notable adverse effects. Mechanistically, hUC-MSC treatment promotes cortical neuronal dendritic development and restores the phosphorylation levels of insulin-like growth factor 1 receptor (IGF-1R) and protein kinase B (Akt). Furthermore, mRNA expression of synaptic plasticity-associated genes GAP-43 and SYP, as well as the anti-inflammatory cytokine IL-10, was significantly upregulated, while the expression of proapoptotic genes Bax and Caspase-3, along with pro-inflammatory cytokines IL-6 and IL-1β, was markedly suppressed.

CONCLUSIONS

These findings suggest that hUC-MSCs may exert neuroprotective effects by modulating the IGF-1/Akt signaling pathway, promoting neuronal development, reducing neuroinflammation, and inhibiting apoptosis, ultimately alleviating core ASD-like symptoms. The therapeutic benefits may stem from paracrine factors secreted by hUC-MSCs or their ability to regulate gene expression linked to neuronal development. Our study provides new insights into ASD pathogenesis and highlights the potential of hUC-MSCs as a novel stem cell-based therapy for ASD.