Abstract
Objective: Local injection of induced pluripotent stem cells (iPS) ameliorates stroke along with teratoma formation and mechanic injury. We hypothesize that intravenously administration may disseminate iPS in the tissues of target and therefore avoid teratoma formation while retaining therapeutic effect. MiR-221 and miR-320 involves in cell adhesion, migration and angiogenesis. They may regulate iPS function. The present study observes the effect of intravenous injected iPS on brain ischemia/reperfusion injury and the roles of miR-221 and miR- 320. Methods: 156 mice were subjected to MCAO for 45 min followed by reperfusion. After 4h reperfusion, they were randomly divided into 6 groups and injected with iPS, con-siRNA-iPS, miR-221-iPS, miR-320-iPS, MEF or PBS intravenously. 12 and 14 mice per group were observed for 2 and 7 days, respectively. Neurologic dysfunction and infarct area were evaluated by neurological impaired use scores and TTC staining. 13 common pro-/anti-inflammatory mediators were measured by reverse transcription real time PCR. Heme oxygenase-1 (HO-1) was observed by immune histochemistry and Western blotting. Results: The survival rates for mice receiving iPS, con-siRNA-iPS, miR-221-iPS, miR-320-iPS, MEF or PBS were 11/12, 10/12, 9/12, 10/12, 8/12 and 9/12 for 2 days and 6/14, 6/14, 1/14, 2/14, 0/14 and 0/14 for 7 days, respectively. iPS decreased neurologic functional disorder and infarct area significantly, compared to animals treated with MEF or PBS. Transfection of iPS with miR-221 or miR-320 but not control siRNA blocked the beneficial function of iPS. iPS increased the ratio of inhibitory/stimulatory inflammatory mediators and HO-1 on day 2. Tracing of fluorescence-labeled cells found iPS and con-siRNA-iPS selectively located in infarct boundary zone. Some iPS differentiated into microglia and astrocytes on day 7. Only in occasion, MEF, miR-221-iPS or miR-320-iPS were found in injured brains. Five additional mice that received iPS were used to observe teratoma formation and were free of teratoma for at least 3 months. Conclusion: Intravenous administered iPS selectively engrafted in the infarction boundary zone and ameliorated brain I/R injury. MiR-221 and miR-320 are essential for the therapeutic effect of iPS.
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