Conditioned medium derived from mesenchymal stem cells overexpressing HPV16 E6E7 dramatically improves ischemic limb |
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| Institution: | 1. Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan;2. Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan;3. Institute of Anatomy, Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan;4. Stem Cell Laboratory, Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan;5. Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan;6. Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan;7. Institute of Biomedical Sciences, Academia Sinica, Taipei 105, Taiwan;1. Department of Bioengineering, University of Washington, Seattle, WA 98195, USA;2. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA;3. Center for Cardiovascular Biology, University of Washington, Seattle, WA 98195, USA;4. Department of Pathology, University of Washington, Seattle, WA 98195, USA;5. Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA;1. Dept of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, T2N 4 N1 Canada;2. Dept of Pharmacology, University of California-Davis, Davis, CA 95616, USA;1. Department of Biochemistry and Molecular Biology, United States;2. Department of Physiology and Biomedical Engineering, United States;2. United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, MD 20705, USA;3. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA |
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| Abstract: | Mesenchymal stem cells (MSCs) have been shown to secrete cytokines and growth factors required for angiogenesis. Previously, we demonstrated that MSCs expressing HPV16 E6E7 mRNA (E6E7-MSCs) increase life span and differentiation potential and maintain without neoplastic transformation. Whether E6E7-MSCs are sources of molecules for enhancing angiogenesis is unknown. We demonstrated that E6E7-MSC-derived conditioned medium (E6E7-CM) enhanced endothelial cell migration and tube formation compared to primary MSC-derived conditioned medium (primary-CM). Moreover, E6E7-MSCs increased AKT activation and enhanced the release of Interleukin-1β (IL-1β) and vascular endothelial growth factor A (VEGFA). Neutralization of E6E7-CM with antibodies against IL-1β or VEGFA abrogated its effect in enhancing endothelial migration and tube formation. Primary-CM, added with IL-1β and VEGFA, enhanced its ability to increase endothelial migration and tube formation. E6E7-CM was shown to increase the ability to improve blood perfusion in a mouse limb ischemia model. Histological analysis revealed that E6E7-CM prohibited muscle loss or fibrosis and increased endothelial cell counts compared to primary-CM. Similarly, the effects of E6E7-CM in improving perfusion in ischemic limb were also contributed by the increase of IL-1β or VEGFA levels. These results suggest that E6E7-MSCs increase the ability to secrete angiogenic factors via AKT activation, and E6E7-CM is abundant in IL-1β and VEGFA levels and thereby increases the ability to improve blood perfusion and prohibit muscle loss or fibrosis in a mouse limb ischemia model. |
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