Tetracycline-regulated expression of VEGF-A in beta cells induces angiogenesis: improvement of engraftment following transplantation.

Détails

ID Serval
serval:BIB_76B961622F68
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Tetracycline-regulated expression of VEGF-A in beta cells induces angiogenesis: improvement of engraftment following transplantation.
Périodique
Cell Transplantation
Auteur(s)
Mathe Z., Dupraz P., Rinsch C., Thorens B., Bosco D., Zbinden M., Morel P., Berney T., Pepper M.S.
ISSN
0963-6897[print], 0963-6897[linking]
Statut éditorial
Publié
Date de publication
2006
Peer-reviewed
Oui
Volume
15
Numéro
7
Pages
621-636
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Early revascularization of pancreatic islet cells after transplantation is crucial for engraftment, and it has been suggested that vascular endothelial growth factor-A (VEGF-A) plays a significant role in this process. Although VEGF gene therapy can improve angiogenesis, uncontrolled VEGF secretion can lead to vascular tumor formation. Here we have explored the role of temporal VEGF expression, controlled by a tetracycline (TC)-regulated promoter, on revascularization and engraftment of genetically modified beta cells following transplantation. To this end, we modified the CDM3D beta cell line using a lentiviral vector to promote secretion of VEGF-A either in a TC-regulated (TET cells) or a constitutive (PGK cells) manner. VEGF secretion, angiogenesis, cell proliferation, and stimulated insulin secretion were assessed in vitro. VEGF secretion was increased in TET and PGK cells, and VEGF delivery resulted in angiogenesis, whereas addition of TC inhibited these processes. Insulin secretion by the three cell types was similar. We used a syngeneic mouse model of transplantation to assess the effects of this controlled VEGF expression in vivo. Time to normoglycemia, intraperitoneal glucose tolerance test, graft vascular density, and cellular mass were evaluated. Increased expression of VEGF resulted in significantly better revascularization and engraftment after transplantation when compared to control cells. In vivo, there was a significant increase in vascular density in grafted TET and PGK cells versus control cells. Moreover, the time for diabetic mice to return to normoglycemia and the stimulated plasma glucose clearance were also significantly accelerated in mice transplanted with TET and PGK cells when compared to control cells. VEGF was only needed during the first 2-3 weeks after transplantation; when removed, normoglycemia and graft vascularization were maintained. TC-treated mice grafted with TC-treated cells failed to restore normoglycemia. This approach allowed us to switch off VEGF secretion when the desired effects had been achieved. TC-regulated temporal expression of VEGF using a gene therapy approach presents a novel way to improve early revascularization and engraftment after islet cell transplantation.
Mots-clé
Animals, Cell Line, Cell Proliferation/drug effects, Gene Expression Regulation/drug effects, Glucose/pharmacology, Graft Survival/drug effects, Insulin/metabolism, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/metabolism, Islets of Langerhans Transplantation/methods, Mice, Neovascularization, Physiologic/drug effects, Protein Synthesis Inhibitors/pharmacology, Tetracycline/pharmacology, Vascular Endothelial Growth Factor A/genetics, Vascular Endothelial Growth Factor A/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 13:41
Dernière modification de la notice
20/08/2019 14:33
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