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Guangying Li1, Longhai Xiao1, Hao Qin1
1Department of Neurosurgery, Zaozhuang Municipal Hospital, Zaozhuang, Shandong, P.R. China.
Abstract:
Exosome and microRNAs (miRs) are implicated in ischemia/reperfusion (I/R) process. In this study, I/R mouse model was established, and exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) were isolated, identified, and injected to I/R mice to observe nerve injury and microglia M1 polarization. The differentially expressed genes in I/R microglia from databases were analyzed, and miRs differentially expressed in exosomes-treated microglia were analyzed by microarray. miR-26b-5p expression in hUCMSCs was intervened. Besides, microglia was extracted and co-cultured with SH-SY5Y or PC12 cells in oxygen-glucose deprivation/reperfusion (OGD/R) models to simulate I/R in vivo. Additionally, Toll-like receptor (TLR) activator GS-9620 was added to microglia. Exosomes alleviated nerve injury and inhibited M1 polarization in microglia. After I/R modeling, CH25H expression in microglia was upregulated but decreased after exosome treatment. miR-26b-5p was upregulated in microglia after exosome treatment and could target CH25H. Reduction in exosomal miR-26b-5p reversed the effects of hUCMSCs-exos on microglia. TLR pathway was activated in microglia after I/R but exosomes prevented its activation. Exosomal miR-26b-5p could repress M1 polarization of microglia by targeting CH25H to inactivate the TLR pathway, so as to relieve nerve injury after cerebral I/R. This investigation may offer new approaches for I/R treatment.
Insights
Human umbilical cord mesenchymal stem cell exosomes carrying miR-26b-5p alleviate nerve injury and microglia M1 polarization in ischemia/reperfusion (I/R) by targeting CH25H and inactivating the TLR pathway.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Ischemia/reperfusion (I/R) injury involves exosomes and microRNAs (miRs).
- Microglia polarization, particularly M1, contributes to nerve damage in I/R.
- Mesenchymal stem cell-derived exosomes show therapeutic potential.
Purpose of the Study:
- To investigate the therapeutic effect of human umbilical cord mesenchymal stem cell (hUCMSC)-derived exosomes on nerve injury and microglia polarization in an I/R mouse model.
- To elucidate the underlying mechanism involving miR-26b-5p, CH25H, and the Toll-like receptor (TLR) pathway.
Main Methods:
- Established an I/R mouse model and isolated/identified hUCMSC-derived exosomes.
- Analyzed differentially expressed genes and miRs in microglia; performed gene intervention and cell co-culture experiments.
- Utilized microarray analysis and targeted gene assays to confirm miR-26b-5p's role and its interaction with CH25H.
Main Results:
- hUCMSC-derived exosomes alleviated nerve injury and inhibited M1 polarization in microglia.
- Exosomes upregulated miR-26b-5p in microglia, which targeted and downregulated CH25H expression.
- miR-26b-5p repressed M1 polarization by inactivating the TLR pathway, thereby mitigating I/R-induced nerve injury.
Conclusions:
- Exosomal miR-26b-5p plays a crucial role in the neuroprotective effects of hUCMSC-derived exosomes.
- The miR-26b-5p/CH25H/TLR pathway is a key mechanism underlying exosome-mediated I/R neuroprotection.
- This study offers novel therapeutic strategies for cerebral I/R injury.
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