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Neural stem cell-derived extracellular vesicles inhibit microglial dysfunction in depression through targeting miR-16-5p/Cxcr4 axis

ABSTRACT: Neural stem cell-derived extracellular vesicles (NSC-EVs) have emerged as promising candidates for neurological disease treatment through delivering bioactive cargoes with therapeutic effects, but their roles in major depressive disorder (MDD) remains poorly understood. Here, we collected NSC-EVs and showed these EVs penetrated the blood-brain-barrier and internalized by brain cells via intravenous injection. NSC-EVs alleviated chronic restraint stress (CRS)-induced depression-like behavioral and pathological alterations presumably through inhibiting inflammatory responses and excessive synaptic pruning of microglia. We next identified miR-16-5p as a key component of NSC-EVs responsible for their therapeutic effects by directly targeting Cxcr4 in microglia. We further demonstrated that either microglial Cxcr4 knockout or Cxcr4 inhibitors treatment significantly mitigated depression-like phenotypes of CRS mice. Thus, our findings suggest NSC-EVs as a novel therapeutic strategy and identified Cxcr4 a potential therapeutic target of MDD.

ORGANISM(S): Mus musculus

PROVIDER: GSE292766 | GEO | 2025/10/25

REPOSITORIES: GEO

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Project description:Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho 0 cells rescued mitochondrial function and increased Rho 0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of proinflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

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Neural stem cell-derived extracellular vesicles inhibit microglial dysfunction in depression through targeting miR-16-5p/Cxcr4 axis

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