Maximizing Ventricular Function With Multimodal Cell-Based Gene Therapy

Background— Angiogenesis is enhanced after transplantation of vascular endothelial growth factor (VEGF)-expressing cells into a myocardial scar. Insulin-like growth factor I (IGF-I) may induce hypertrophy and inhibit apoptosis. We evaluated the effect of cell-based IGF-I and VEGF multigene therapy on left ventricular (LV) function, cell survival, and apoptosis after bone marrow cell (BMC) transplantation. Methods and Results— Female Lewis rats underwent left anterior descending ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), IGF-I (BMC+IGF-I), VEGF and IGF-I (BMC+VEGF+IGF-I), or medium without cells (control) (n=4 per group×5 groups×4 time points). Three days and 1, 2, and 4 weeks after transplantation, VEGF and IGF-I expression was quantitated by real-time polymerase chain reaction, cell survival by polymerase chain reaction for sry2, apoptosis by TUNEL staining, LV function by echocardiography and myosin heavy chain, and light chain and troponin I by Western blot. One week after transplantation, IGF-I expression in the scar and border zone was greatest in BMC+IGF-I and BMC+VEGF+IGF-I rats ( P <0.05). VEGF expression in the scar and border zone was greatest in BMC+VEGF and BMC+VEGF+IGF-I hearts ( P <0.05). Transplanted cell survival was lowest in BMC, intermediate in BMC+VEGF and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I ( P <0.05). Apoptotic indices were significantly reduced in BMC+VEGF+IGF-I, BMC+VEGF, and BMC+IGF-I ( P <0.05). Two and 4 weeks after transplantation, LV ejection fraction was lowest in control, intermediate in BMC, BMC+VEGF, and BMC+IGF-I, and greatest in BMC+VEGF+IGF-I ( P <0.05). Conclusions— Transplantation of VEGF- and IGF-I-expressing BMC reduced apoptosis, maximized transplanted cell survival, and enhanced LV function. Multimodal cell-based gene therapy may maximize the benefits of cell transplantation.

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Combined transmyocardial revascularization and cell-based angiogenic gene therapy increases transplanted cell survival

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00178.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. H3311-H3316 ◽

Cited By ~ 19

Author(s):

Dan Spiegelstein ◽

Christopher Kim ◽

Yaoguang Zhang ◽

Guangming Li ◽

Richard D. Weisel ◽

...

Keyword(s):

Gene Therapy ◽

Growth Factor ◽

Cell Survival ◽

Bone Marrow Cells ◽

Combined Therapy ◽

Left Ventricular ◽

Lv Function ◽

Angiogenic Growth Factors ◽

Myocardial Repair ◽

Transmyocardial Revascularization

We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) before transplantation of bone marrow cells (BMCs) or BMC-expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Female Lewis rats underwent coronary ligation 3 wk before creation of 10 needle TMR channels (3 groups) or no TMR (3 groups), followed by transplantation of 3 × 106 male donor BMCs, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) (BMC + VBI), or medium alone. At 1, 3, and 7 days, we evaluated transplanted cell survival, vascular densities, and left ventricular (LV) function ( N = 4 per group × 6 groups × 3 time points). At 3 days, vascular densities in the scar were increased by TMR + BMC + VBI and by BMC + VBI ( P < 0.05), and at 7 days, vascular densities were greatest in rats receiving TMR + BMC + VBI ( P < 0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC + VBI. Combined therapy with TMR + BMC + VBI resulted in the greatest cell survival at 3 days ( P < 0.05) versus BMC. After 7 days, LV ejection fraction (LVEF) was lowest in rats receiving neither BMC nor TMR and greatest in rats receiving TMR + BMC + VBI ( P = 0.004). We concluded that mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis, and LV function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair.

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