Abstract 3816: Injection of GSK-3β Overexpressing Bone Marrow Derived Mesenchymal Stem Cells Attenuates Cardiac Dysfunction after Myocardial Infarction
Glycogen synthase kinase 3β (GSK-3β) induces expression of cardiac markers in mesenchymal stem cells (MSCs). We examined whether injection of ex vivo-modified GSK-3β overexpressing MSCs improves cardiac dysfunction after myocardial infarction (MI). Mouse MSCs were transduced with adenovirus harboring LacZ or GSK-3β (LacZ-MSC or GSK-MSC). MI was induced by coronary ligation and thirty μL of saline alone or MSCs (1.5 x 105 cells) were injected into the MI border zone just after coronary ligation. In saline injected MI mice, a progressive increase in left ventricular end diastolic dimension (LVEDD) and a progressive decrease in LV ejection fraction (LVEF) and LV fractional shortening (%FS) were observed compared with sham (Table⇓). LacZ-MSC or GSK-MSC attenuated increases in LVEDD at 2 and 12 weeks. However, LVEF and %FS were significantly greater in GSK-MSC than in LacZ-MSC group at 2 and 12 weeks (Table⇓). Heart weight/body weight (HW/BW) in GSK-MSC (4.4±0.1) group was significantly smaller than that in LacZ-MSC (5.1±0.2) and saline (5.0±0.2) groups and not significantly different from that in sham group (4.1±0.0), suggesting that cardiac remodeling was attenuated by GSK-MSC. To further confirm the effect of GSK-3β, MSCs acquired from inducible GSK-3β (tet-OFF) mice were injected into the MI mice fed with or without doxycycline (Dox), where expression of GSK-3β transgene was abrogated by Dox treatment in situ. After two weeks of MI, both LVEF (61.5±2.2, 37.4±7.1, p<0.01) and %FS (27.6±1.4, 15.4±3.2, p<0.001) were significantly greater in Dox (−) (n=13) than in Dox (+) mice (n=9). These results suggest that ex vivo introduction of GSK-3β improves the effect of MSC injection, thereby attenuating LV dysfunction after MI. Furthermore, in situ Dox-regulatable expression of GSK-3β also facilitated the therapeutic effect of MSCs injection.