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(Circulation. 2005;112:I-123 – I-128.)
© 2005 American Heart Association, Inc.

Cell Transplantation and Tissue Engineering

Maximizing Ventricular Function With Multimodal Cell-Based Gene Therapy

Terrence M. Yau, MD, MSc; Christopher Kim, BSc; Guangming Li, MD; Yaoguang Zhang, MD; Richard D. Weisel, MD; Ren-Ke Li, MD, PhD

From the Division of Cardiovascular Surgery, Toronto General Hospital, Department of Surgery, University of Toronto, Heart & Stroke Foundation/Richard Lewar Centre of Excellence, Toronto, Ontario, Canada.

Correspondence to Dr Terrence M. Yau, Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, 4N-470, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail terry.yau{at}utoronto.ca

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 groupx5 groupsx4 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.

Key Words: cells • gene therapy • growth substances • angiogenesis