Bone marrow-derived mesenchymal stem cells overexpressed with miR-182-5p protects against brain injury in a mouse model of cerebral ischemia |
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| Affiliation: | 1. Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha 410011, China;2. Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410011, China;1. Yale School of Medicine, 100 York St. Suite 1N, New Haven, CT 06511, United States;2. Stroke Trials Unit, Mental Health and Clinical Neuroscience, University of Nottingham, Nottingham NG7 2UH, UK;3. Warren Alpert Medical School of Brown University, Providence, RI, United States;4. Fred Hutchinson Cancer Research Center, Seattle, WA, United States;5. Yale School of Public Health, New Haven, CT, United States;1. Department of Cardiology, Sincan State Hospital Ankara, Sincan, Ankara 06933, Turkey;2. Department of Cardiology, Adiyaman University Education and Research Hospital, Adiyaman, Turkey;1. Neurology and Stroke Unit, AORN “A. Cardarelli”, Naples, Italy;2. Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy;3. Internal Medicine and Immunology, Federico II University, Naples;1. Department of Neurology, University of Missouri, 1 Hospital Drive, Columbia, MO, 65212;2. Department of Otolaryngology, Head and Neck Surgery, 1 University of Missouri, One Hospital Drive, Columbia, MO, 65212;3. Division of Neurosurgery, University of Missouri, 1 Hospital Drive, MO, 65212;4. Zeenat Qureshi Stroke Institute, St. Cloud, Minnesota;1. Division of Cardiovascular Medicine, Electrophysiology Section, University of Pennsylvania, 3400 Spruce Street, 9 Founders Cardiology, Philadelphia, PA, USA;2. Epidemiological Cardiology Research Center, Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA;3. Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA;4. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA;5. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA;6. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA |
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| Abstract: | BackgroundToll-like receptor 4 (TLR4) plays a critical role in ischemic brain injury by mediating the inflammatory response. The microRNA miR-185-5p suppresses inflammatory signaling by targeting TLR4. This study investigates whether overexpressing miR-182-5p in bone marrow-derived mesenchymal stem cells (BM-MSCs) could potentiate the neuroprotective effects of BM-MSCs in a mouse model of ischemic brain injury.MethodsWe isolated BM-MSCs from mice, transfected the cells with miR-182-5p mimic, determined their MSC lineage through flow cytometry analysis of surface markers, examined miR-182-5p and TLR4 expression levels, and injected them into mice undergone middle cerebral artery occlusion (MCAO). MSC transplanted mice were subjected to behavior assays to determine cognitive and motor functions and biochemical analysis to determine neuroinflammation and TLR4/NF-κB in the ischemic hemisphere.ResultsWe found that BM-MSCs overexpressing miR-182-5p showed reduced TLR4 expression without affecting their MSC lineage. Mice transplanted with miR-182-5p overexpressing BM-MSCs after MCAO showed significantly improved cognitive and motor functions and reduced neuroinflammation, including suppressed microglial M1 polarization, reduced inflammatory cytokines, and inhibited TLR4/ NF-κB signaling.ConclusionOur findings suggest that overexpressing miR-182-5p in BM-MSCs can enhance the neuroprotective effects of BM-MSCs against ischemic brain injury by suppressing TLR4-mediated inflammatory response. |
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