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Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke.

ABSTRACT: The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced prominent atrophic changes in the striatum and led to proliferation of neural progenitor cells in the subventricular zone (SVZ) and the surrounding areas of the striatum (SVZ + striatum) of MCAO mice. The mBMSC and EA treatment markedly enhanced mature brain-derived neurotrophic factor (mBDNF) expression in the SVZ + striatum and hippocampus of mice with MCAO, and combined treatment enhanced neurotrophin-4 (NT4) expression. The number of mBDNF- and NT4-positive neurons in the SVZ + striatum and hippocampus increased following EA treatment. Combined treatment led to an increase in the expression levels of phosphorylated cAMP response element binding protein in the neuroblasts of the striatum. Our results indicate that combined MSC and EA treatment may lead to a better therapeutic effect via co-regulation of neurotrophic factors in the brain, by regulating neurogenesis more than single therapy.

SUBMITTER: Kim YR

PROVIDER: S-EPMC5794924 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke.

Kim Yu Ri YR Ahn Sung Min SM Pak Malk Eun ME Lee Hong Ju HJ Jung Da Hee DH Shin Yong-Il YI Shin Hwa Kyoung HK Choi Byung Tae BT

Scientific reports 20180201 1

The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced promine ...[more]

PMID: 29391466

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Project description:Background: The complicated molecular mechanisms underlying the therapeutic effect of electroacupuncture (EA) on ischemic stroke are still unclear. Recently, more evidence has revealed the essential role of the microRNA (miRNA)-mRNA networks in ischemic stroke. However, a systematic analysis of novel key genes, miRNAs, and miRNA-mRNA networks regulated by EA in ischemic stroke is still absent. Methods: We established a middle cerebral artery occlusion (MCAO) mouse model and performed EA therapy on ischemic stroke mice. Behavior tests and measurement of infarction area were applied to measure the effect of EA treatment. Then, we performed RNA sequencing to analyze differentially expressed genes (DEGs) and functional enrichment between the EA and control groups. In addition, a protein-protein interaction (PPI) network was built, and hub genes were screened by Cytoscape. Upstream miRNAs were predicted by miRTarBase. Then hub genes and predicted miRNAs were verified as key biomarkers by RT-qPCR. Finally, miRNA-mRNA networks were constructed to explore the potential mechanisms of EA in ischemic stroke. Results: Our analysis revealed that EA treatment could significantly alleviate neurological deficits in the affected limbs and reduce infarct area of the MCAO model mice. A total of 174 significant DEGs, including 53 upregulated genes and 121 downregulated genes, were identified between the EA and control groups. Functional enrichment analysis showed that these DEGs were associated with the FOXO signaling pathway, NF-kappa B signaling pathway, T-cell receptor signaling pathway, and other vital pathways. The top 10 genes with the highest degree scores were identified as hub genes based on the degree method, but only seven genes were verified as key genes according to RT-qPCR. Twelve upstream miRNAs were predicted to target the seven key genes. However, only four miRNAs were significantly upregulated and indicated favorable effects of EA treatment. Finally, comprehensive analysis of the results identified the miR-425-5p-Cdk1, mmu-miR-1186b-Prc1, mmu-miR-434-3p-Prc1, and mmu-miR-453-Prc1 miRNA-mRNA networks as key networks that are regulated by EA and linked to ischemic stroke. These networks might mainly take place in neuronal cells regulated by EA in ischemic stroke. Conclusion: In summary, our study identified key DEGs, miRNAs, and miRNA-mRNA regulatory networks that may help to facilitate the understanding of the molecular mechanism underlying the effect of EA treatment on ischemic stroke.

Project description:ObjectiveThis study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship.MethodsThe levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1β, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment.ResultsThe hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1β but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×107/kg treatment showed the best therapeutic effect, followed by the 1×107/kg treatment, and the worst is 0.5×107/kg treatment from the test of balance beam, forelimb muscle strength, limb placement and the infarct area of the rat brain tissues.ConclusionThe hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurological/motor function and reduce the size of cerebral infarction in rats.

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Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke.

Publications

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke.

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