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Inflammation Modifies miR-21 Expression Within Neuronal Extracellular Vesicles to Regulate Remyelination Following Spinal Cord Injury.

ABSTRACT: Cell‒cell communication following spinal cord injury (SCI) plays a key role in remyelination and neurological recovery. Although communication between neuron-neural stem cells (NSCs) affects remyelination, its precise mechanism remains unclear. The present study investigated the biological effects of extracellular vesicles (EVs) derived from neurons on the differentiation of NSCs and the remyelination of axons in a rat model for SCI. We found that that EVs derived from neurons promoted the differentiation of NSCs into oligodendrocytes and the remyelination of axons in SCI rats. However, neuron-derived EVs lost their biological effects after inflammatory stimulation of these neurons from which they originate. Further analysis demonstrated that the inflammatory stimulation on neurons upregulated miR-21 within EVs, which targeted SMAD 7 and upregulated the TGF-β/SMAD2 signaling pathway, resulting in an excess of astrocytic scar boundaries and in remyelination failure. Moreover, these effects could be abolished by miR-21 inhibitors/antagomirs. Considered together, these results indicate that inflammatory stimulation of neurons prevents remyelination following SCI via the upregulation of miR-21 expression within neuron-derived EVs, and this takes place through SMAD 7-mediated activation of the TGF-β/SMAD2 signaling pathway. Graphical Astract.

SUBMITTER: Han T

PROVIDER: S-EPMC10390616 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Inflammation Modifies miR-21 Expression Within Neuronal Extracellular Vesicles to Regulate Remyelination Following Spinal Cord Injury.

Han Tianyu T Song Peiwen P Wu Zuomeng Z Liu Yunlei Y Ying Wang W Shen Cailiang C

Stem cell reviews and reports 20230531 6

Cell‒cell communication following spinal cord injury (SCI) plays a key role in remyelination and neurological recovery. Although communication between neuron-neural stem cells (NSCs) affects remyelination, its precise mechanism remains unclear. The present study investigated the biological effects of extracellular vesicles (EVs) derived from neurons on the differentiation of NSCs and the remyelination of axons in a rat model for SCI. We found that that EVs derived from neurons promoted the diffe ...[more]

PMID: 37256514

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Project description:BackgroundSpinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI.MethodsCD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications.ResultsCD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4.ConclusionsCD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy.

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Inflammation Modifies miR-21 Expression Within Neuronal Extracellular Vesicles to Regulate Remyelination Following Spinal Cord Injury.

Publications

Inflammation Modifies miR-21 Expression Within Neuronal Extracellular Vesicles to Regulate Remyelination Following Spinal Cord Injury.

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