**5. Conclusions**

Genetic modification increases the therapeutic efficacy of stem cells by improving their survival, enhancement of paracrine activity and by supporting their angiomyogenic differentiation (Tang et al. 2004). A combined cell and gene therapy approach reverses the deteriorating function of the infarcted heart (Mangi et al. 2003; Matsumoto et al. 2005) and offers an extended and localized expression of the transgene product. From the clinical standpoint, the strength of stem cell therapy and gene therapy approaches lies in their combined application to achieve stable therapeutic benefits. The viability and persistence of the genetically modified stem cells and their derivative graft in the heart can be significantly enhanced by restoration of regional blood flow *via* biological bypass surgery which is achieved by neovascularization of the infarcted heart. The new emerging pro-angiogenic role of angiopoietin-1 independent of VEGF, in addition to its well recognized participation in the angiogenic cascade as a maturation factor, makes angiopoietin-1 as a growth factor of choice for ex-vivo stem cell based gene therapy which can be used independently or in combination with VEGF to support angiomyogenic recovery of the infarcted heart.

#### **6. Acknowledgements**

This work was supported by National Institutes of Health Grants #R37-HL074272;HL-080686;HL-087246(M.A) and HL-087288;HL-089535; HL106190-01 (Kh.H.H).

#### **7. References**


al. 2008). Besides, we also opted to replace Vegf with survival signaling molecule Akt to support survival of the genetically modified mesenchymal stem cells (Jiang et al. 2006). Our choice of transgene combination of angiopoietin-1 and Akt achieved maximum beneficial effects in terms of donor stem cell survival and angiomyogenic repair of the infarcted heart. More importantly, the therapeutic benefits in terms of cell graft survival, stability of newly formed blood vessels and global cardiac function were stable for up to 3 months (Shujia et al. 2008). A more recent study has used sendai viral vector for transduction of mesenchymal stem cells, however, it remains difficult to see the advantages of mesenchymal stem cells modified with sendai vector harboring human angiopoietin-1 gene (Piao, Wang et al.)

Genetic modification increases the therapeutic efficacy of stem cells by improving their survival, enhancement of paracrine activity and by supporting their angiomyogenic differentiation (Tang et al. 2004). A combined cell and gene therapy approach reverses the deteriorating function of the infarcted heart (Mangi et al. 2003; Matsumoto et al. 2005) and offers an extended and localized expression of the transgene product. From the clinical standpoint, the strength of stem cell therapy and gene therapy approaches lies in their combined application to achieve stable therapeutic benefits. The viability and persistence of the genetically modified stem cells and their derivative graft in the heart can be significantly enhanced by restoration of regional blood flow *via* biological bypass surgery which is achieved by neovascularization of the infarcted heart. The new emerging pro-angiogenic role of angiopoietin-1 independent of VEGF, in addition to its well recognized participation in the angiogenic cascade as a maturation factor, makes angiopoietin-1 as a growth factor of choice for ex-vivo stem cell based gene therapy which can be used independently or in

combination with VEGF to support angiomyogenic recovery of the infarcted heart.

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**Part 2** 

**Pathogenesis of Myocarditis** 

