Mesenchymal Stem Cell (MSC) Transplantation Accompanied by Activation of Invariant Natural Killer T Cells Further Ameliorates Post-infarct Cardiac Remodeling in Mice.

Background: The purpose of this study was to examine the effect of mesenchymal stromal/stem cells (MSCs) on the infiltration of iNKT cells and further observe whether the activation of invariant natural killer T (iNKT) cells could assist the therapeutic action of MSCs on ventricular remodeling.

Methods: Mice with MI were used. qRT-PCR for Va14Ja18 (a special marker of iNKT cell for C57BL/6) was carried out. Gene expressions of Va14Ja18 were analyzed. Then, the experiment was performed in five groups: MI+Me, MI+MSCs, MI+MSCs+indome, MI+a-GC and MI+MSCs+a-GC. After 28 days, heart tissue fibrosis was accessed by Masson trichrome dyeing and apoptosis was evaluated by TUNEL staining and western blotting for caspase-3 protein.

Results: The number of iNKT cells infiltrating into the PLV significantly increased at day 7 after MI (1.72-fold changes from baseline, P<0.05), but almost returned to the baseline level at days 14 and 28. Compared to the MI+Me group (1.76±0.20-fold), iNKT cell infiltration was significantly suppressed at day 7 in MI+MSCs (1.25±0.29-fold, P<0.05) and MI+cMe groups (1.19±0.25-fold, P<0.05). In MI+cMe+indome and MI+cMe+PGE2 groups, the changes of iNKT cell infiltration were 1.74- and 1.04-fold, respectively (vs. 1.20-fold in the MI+cMe group, P<0.05). After the treatment by the combination of MSC transplantation and iNKT cell activation, myocyte apoptosis and interstitial fibrosis in PLV were both significantly attenuated.

Conclusions: In the infarcted mouse model, MSCs suppressed the infiltration of iNKT cells by secreting PGE2. Activating iNKT cells could assist the therapeutic effect of MSCs on ventricular remodeling, with attenuated apoptosis and interstitial fibrosis. Therapies designed to activate iNKT cells before MSC transplantation might be beneficial to enhance the effectiveness of MSCs in the post-MI heart. This new approach brought forth from this study could offer a new path of immunotherapeutic interventions for infarcted hearts.