Abstract 1857: Overexpression of MEF2c and IGF-1 in Transplanted Mesenchymal Stem Cells Increases Myogenic Differentiation, Cell Survival and LV Function in Rats
Background: We have reported that myocyte enhancer factor 2c (MEF2c) augments myogenic differentiation of cultured mesenchymal stem cells (MSC). Insulin-like growth factor (IGF-1) is known to increase cellular proliferation and decrease apoptosis.
Hypothesis: We hypothesized that transfection of MSC with MEF2c and IGF-1 would increase the efficacy of MSC transplantation in infarcted hearts.
Methods: Female Lewis rats underwent LAD ligation 3 weeks before transplantation of 3×106 male donor MSC, MSC transfected with MEF2c (MSC+MEF2c), IGF-1 (MSC+IGF-1), MEF2c and IGF-1 (MSC+MEF2c+IGF-1) or medium (Control) (N=6 per group per timepoint). MSC were characterized by flow cytometry and immunohistochemistry. Two and 4 weeks after transplantation, transgene expression and cell survival were quantitated by PCR, vascular densities by histology, and LV function by echocardiography.
Results: MSC expressed 98±1.8% CD90, 94±1.6% Sca-1, 11±1.6% CD45 and 1±0.3% CD34. At 2 weeks, MEF2c expression in the scar and border zone was greatest in MSC+MEF2c and MSC+MEF2c+IGF-1 (P<0.01), but had returned to baseline by 4 weeks. IGF-1 expression in the scar and border zone was greatest at 2 and 4 weeks in MSC+IGF-1 and MSC+MEF2c+IGF-1 (P<0.01). At 2 and 4 weeks, cell survival was lowest in MSC and MSC+MEF2c and greatest in MSC+IGF-1 and MSC+MEF2c+IGF-1 (P<0.05). At 2 weeks, Ki67 positive cells were more frequent in the scar and border zone compared with normal myocardium in all groups (P<0.05), but did not differ between groups. At 2 and 4 weeks, vascular densities in the scar and border zone were lowest in Control, MSC and MSC+MEF2c and highest in MSC+MEF2c+IGF-1 and MSC+IGF-1 (P<0.05). Two and 4 weeks after transplantation, LV ejection fraction was lowest in Control, intermediate in MSC and MSC+IGF-I, greater in MSC+MEF2c and greatest in MSC+MEF2c+IGF-I (P<0.01).
Conclusions: Transplantation of MSC transfected with MEF2c and IGF-I augments myogenic differentiation, improves cell survival and enhances LV function. While transplantation of unmodified cells is safe and may marginally increase LVEF in humans, the next generation of cell therapies may utilize cells engineered to increase post-implantation myogenic differentiation and survival.