Stem Cells from Human Exfoliated Deciduous Teeth Attenuate Depression-Like Behaviors in CUMS Rats by Suppressing Neuroinflammation and Enhancing Synaptic Plasticity

Purpose: This study aimed to evaluate the therapeutic potential of stem cells from human exfoliated deciduous teeth (SHED) against depression and to elucidate the underlying mechanisms involving neuroinflammation and synaptic plasticity in a rat model of chronic unpredictable mild stress (CUMS). Methods: cells/rat); a fluoxetine group served as positive control. Depressive-like behaviors were assessed through sucrose preference, forced swimming, open field, and Y-maze tests. Post-behavioral molecular analyses in the hippocampus and prefrontal cortex included qRT-PCR and ELISA for key inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10, iNOS, Arg1, NLRP3, Caspase-1) and neuroplasticity markers (BDNF, TrkB, PSD95). Microglial activation and polarization were examined by immunofluorescence. Hippocampal transcriptomic profiling was conducted via RNA sequencing. Results: SHED transplantation rapidly ameliorated CUMS-induced behavioral deficits, showing efficacy comparable to fluoxetine but with a notably faster onset. Mechanistically, SHED potently attenuated neuroinflammation by reducing hippocampal and cortical levels of pro inflammatory cytokines and by promoting a phenotypic shift in microglia from the M1 to the M2 state, as evidenced by morphology and marker expression. Transcriptomic analysis revealed that SHED treatment upregulated gene sets related to postsynaptic density, while downregulating the NOD like receptor (NLRP3 inflammasome) signaling pathway. At the molecular level, SHED enhanced the expression of key synaptic protein (PSD95) and restored the impaired BDNF/TrkB signaling axis in stress-vulnerable brain regions. Conclusion: SHED exerts rapid and potent antidepressant effects in the CUMS model through a convergent dual mechanism: suppressing neuroinflammation via microglial reprogramming and inflammasome inhibition, and enhancing structural and functional synaptic plasticity. These robust preclinical findings strongly support SHED as a novel, mechanism-based, cell therapeutic strategy for major depressive disorder.