UNIGE document Scientific Article
previous document  unige:37007  next document
add to browser collection
Title

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

Authors
Mathe, Zoltan
Rinsch, Chris
show hidden authors show all authors [1 - 9]
Published in Cell Transplantation. 2006, vol. 15, no. 7, p. 621-36
Abstract 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.
Keywords AnimalsCell LineCell Proliferation/drug effectsGene Expression Regulation/drug effectsGlucose/pharmacologyGraft Survival/drug effectsInsulin/metabolismInsulin-Secreting Cells/cytology/metabolismIslets of Langerhans Transplantation/methodsMiceNeovascularization, Physiologic/drug effectsProtein Synthesis Inhibitors/pharmacologyTetracycline/pharmacologyVascular Endothelial Growth Factor A/genetics/metabolism
Identifiers
PMID: 17176614
Full text
Structures
Research group La transplantation d'îlots de Langerhans (623)
Citation
(ISO format)
MATHE, Zoltan et al. Tetracycline-regulated expression of VEGF-A in beta cells induces angiogenesis: improvement of engraftment following transplantation. In: Cell Transplantation, 2006, vol. 15, n° 7, p. 621-36. doi: 10.3727/000000006783981675 https://archive-ouverte.unige.ch/unige:37007

394 hits

0 download

Update

Deposited on : 2014-05-30

Export document
Format :
Citation style :