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Diabetologia. 2018 Aug;61(8):1804-1810. doi: 10.1007/s00125-018-4646-7. Epub 2018 May 22.

Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation.

Author information

1
Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, 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
Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. Harry.Heimberg@vub.be.
7
Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. Nico.De.Leu@vub.be.
8
Department of Endocrinology, UZ Brussel, Brussels, Belgium. Nico.De.Leu@vub.be.
9
Department of Endocrinology, ASZ Aalst, Aalst, Belgium. Nico.De.Leu@vub.be.

Abstract

AIMS/HYPOTHESIS:

The 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.

METHODS:

Mouse 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.

RESULTS:

At 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/INTERPRETATION:

Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.

KEYWORDS:

Cell therapy; Diabetes; Gene delivery; Graft revascularisation; Islet transplantation; Messenger RNA; Pancreatic beta cell; RNA delivery; VEGFA

PMID:
29789879
DOI:
10.1007/s00125-018-4646-7
[Indexed for MEDLINE]

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