Suppression of miR-181a attenuates H(2)O(2)-induced death of mesenchymal stem cells by maintaining hexokinase II expression

BACKGROUND: Low survival rate of transplanted cells compromises the efficacy of cell therapy. Hexokinase II (HKII) is known to have anti-apoptotic activity through its interaction with mitochondria. The objective was to identify miRNAs targeting HKII and investigate whether miRNA-mediated modulation of HKII could improve the survival of mesenchymal stem cells (MSCs) exposed to H(2)O(2). The expression of HKII in MSCs exposed to H(2)O(2) was evaluated, and HKII-targeting miRNA was screened based on miRNA-target prediction databases. The effect of H(2)O(2) on the expression of the selected HKII-targeting miRNA was examined and the effect of modulation of the selected HKII-targeting miRNA using anti-miRNA on H(2)O(2)-induced apoptosis of MSC was evaluated. RESULTS: H(2)O(2) (600 μM) induced cell death of MSCs and decreased mitochondrial HKII expression. We have identified miR-181a as a HKII-targeting miRNA and H(2)O(2) increased the expression of miR-181a in MSCs. Delivery of anti-miR-181a, which neutralizes endogenous miR-181a, significantly attenuated H(2)O(2)-induced decrease of HKII expression and disruption of mitochondrial membrane potential, improving the survival of MSCs exposed to H(2)O(2). CONCLUSIONS: These findings suggest that H(2)O(2)-induced up-regulation of miR-181a contributes to the cell death of MSCs by down-regulating HKII. Neutralizing miR-181a can be an effective way to prime MSCs for transplantation into ischemic tissues.