Abstract 16002: In Situ Expression of Gsk-3β in Mesenchymal Stem Cells Phase-Dependently Affects the Efficiency of Cell Based Therapy for Chronic Myocardial Infarction
Overexpression of glycogen synthase kinase-3β (GSK-3β) in bone marrow derived mesenchymal stem cells (MSCs) enhances the efficiency of cell based therapy (CBT) in the mouse model of myocardial infarction (MI). Since GSK-3β regulates proliferation, death, and differentiation of MSCs in a time-dependent manner, we investigated how the timing of GSK-3β expression affects the efficiency of CBT. We isolated MSCs from transgenic mice with Tet-off-GSK-3β expression and injected them into the border zone of the post-MI mouse heart. MSCs isolated from green fluorescence protein mice (GFP-MSC) were injected as a control. Expression of GSK-3β in situ was controlled with daily injection of Dox with three protocols, namely Group 1 (no injection), Group 2 (at 0–2 weeks) and Group 3 (at 2–12 weeks), where GSK-3β was expressed in MSCs in situ constitutively, only at a late phase, or only at an acute phase, respectively. MI size at 12 weeks was decreased significantly in all groups (Group 1, 18±4% Group 2, 25±5%; Group 3, 28±4%, p<0.05), compared to the control GFP-MSC group (43±5%). At 12 weeks, left ventricular fractional shortening (LVFS) was significantly (p<0.05) greater in Group 1 (24±1%) and Group2 (26±2%) than in the GFP-MSC group, but there was no significant difference between Group 3 (20±1%) and the GFP-MSC group (14±2%), suggesting that prolonged expression of GSK-3β in MSCs, especially at the chronic phase of MI is required for functional improvement. The LV wall was significantly thicker in Groups 1 and 3 (0.59±0.05 and 0.56±0.04 mm, p<0.01), but there was no significant difference between Group 2 and the GFP-MSC group (0.48±0.04 and 0.32±0.03 mm). c-kit positive cells were significantly increased only in Group 1 (p<0.01), whereas Ki67 positive myocytes were increased only in Group 3 (p<0.01), suggesting that early activation of GSK-3β is essential for proliferation of MSCs or cardiomyocytes and increases in wall thickness. In summary, in situ activation of GSK-3β in MSCs during the early (<2 weeks) phase of MI contributes to cell proliferation and increases in LV wall thickness, whereas that during the late (>2 weeks) phase is essential for the overall improvement of LV function, suggesting that GSK-3β has phase-dependent functions in MSCs during CBT.
- © 2010 by American Heart Association, Inc.