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Human placenta mesenchymal stem cells expressing exogenous kringle1-5 protein by fiber-modified adenovirus suppress angiogenesis

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Abstract

Anti-angiogenesis gene therapy is considered a promising treatment for excessive vascularization. Mesenchymal stem cell (MSC)-based gene therapy may enhance the effect of anti-angiogenesis by maintaining a long therapeutic period in vivo. However, transduction efficiencies and transgene expression in MSC-based gene therapy should be improved. Here we report human placenta-derived MSC (HPMSC)-based gene therapy using a fiber-modified adenoviral vector carrying the kringle1-5 gene to maintain long-term survival and effectively suppress angiogenesis both in vitro and in vivo. HPMSCs infected by the adenoviral vector were transduced at high efficiency with a low multiplicity of infection, and the infected HPMSCs expressed exogenous kringle1-5 protein in vitro and in vivo. Infected HPMSCs were detected at 2 weeks in vivo by fluorescence imaging and immunohistochemistry of reporter gene expression. Importantly, the microvessel growth of aortic rings in vitro was inhibited by administration of infected HPMSCs expressing kringle1-5 protein (K1-5-HPMSCs) at day 6. In Matrigel plugs combined with K1-5-HPMSCs, microvessel density was decreased as detected by immunohistochemistry and blood flow was decreased as detected by the power Doppler contrast enhanced at day 14. The fiber-modified adenovirus is an effective gene vector for HPMSC-based gene therapy, which may be a promising strategy for cancer anti-angiogenesis.

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Zixuan Zhao, Xinyi Chen, … Hanry Yu

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Acknowledgements

This work was supported by grants from Specialized Research Fund for the Doctoral Program of Higher Education (No. 20092307110018); The Key Program of the Heilongjiang Provincial Science and Technology Committee (No. GC10C302); Programs Foundation of the Department of Education of Heilongjiang Province (No. 12511330); Programs Foundation of the Affiliated Tumor Hospital of Harbin Medical University (No. JJZ2011-06); Programs Foundation of the First Affiliated Hospital of Harbin Medical University (No. 2013B19); Programs Foundation of the Department of Health Heilongjiang Province (No. 2012661); and Programs Foundation of Natural Science of the Heilongjiang (No. D201272).We thank Yong Wang (Esaote Shenzhen Medical Equipment) for the help in the contrast imaging of the Matrigel plug models.

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Correspondence to C Wu.

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Chu, Y., Liu, H., Lou, G. et al. Human placenta mesenchymal stem cells expressing exogenous kringle1-5 protein by fiber-modified adenovirus suppress angiogenesis. Cancer Gene Ther 21, 200–208 (2014). https://doi.org/10.1038/cgt.2014.19

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  • DOI: https://doi.org/10.1038/cgt.2014.19

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