Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation |
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Authors: | Willem Staels Yannick Verdonck Yves Heremans Gunter Leuckx Sofie De Groef Carlo Heirman Eelco de Koning Conny Gysemans Kris Thielemans Luc Baeyens Harry Heimberg Nico De Leu |
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Affiliation: | 1.Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel,Brussels,Belgium;2.Department of Paediatrics, Division of Paediatric Endocrinology,Ghent University,Ghent,Belgium;3.Laboratory of Molecular and Cellular Therapy,Vrije Universiteit Brussel,Brussels,Belgium;4.Department of Medicine, Section of Endocrinology,Leiden University Medical Center,Leiden,the Netherlands;5.Laboratory of Clinical and Experimental Endocrinology,Katholieke Universiteit Leuven,Leuven,Belgium;6.Department of Endocrinology,UZ Brussel,Brussels,Belgium;7.Department of Endocrinology,ASZ Aalst,Aalst,Belgium |
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Abstract: | Aims/hypothesisThe initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.MethodsMouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.ResultsAt day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?0.001]).Conclusions/interpretationVegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants. |
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