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Mol Ther Methods Clin Dev. 2017 Jun 23;6:102-111. doi: 10.1016/j.omtm.2017.06.005. eCollection 2017 Sep 15.

Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke.

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Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
Department of Pharmacology, Tokyo Dental College, Tokyo 101-0061, Japan.
Department of Cell and Gene Therapy, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
JCR Pharmaceuticals Co., Ltd., Hyogo, 659-0021, Japan.


Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.


adeno-associated virus; focal cerebral ischemia; gene transfer; interleukin-10; intravenous transplantation; mesenchymal stem cell; neuroprotection

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