Tetracycline-Regulated Expression of VEGF-A in Beta Cells Induces Angiogenesis: Improvement of Engraftment following Transplantation
| Autor: | Thierry Berney, Z Mathe, Domenico Bosco, Michael S. Pepper, Chris Rinsch, Philippe Dupraz, Philippe Morel, Marie Zbinden, Bernard Thorens |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Angiogenesis medicine.medical_treatment Genetic enhancement Islets of Langerhans Transplantation lcsh:Medicine Gene Expression Regulation/drug effects Graft Survival/drug effects Cell Proliferation/drug effects Mice Islets of Langerhans Transplantation/methods 0302 clinical medicine Vascular Endothelial Growth Factor A/genetics/metabolism Insulin-Secreting Cells Insulin ddc:576.5 Protein Synthesis Inhibitors ddc:617 Graft Survival Neovascularization Physiologic/drug effects Glucose/pharmacology Protein Synthesis Inhibitors/pharmacology Insulin-Secreting Cells/cytology/metabolism Beta cell Cell type Insulin/metabolism Biomedical Engineering Neovascularization Physiologic Biology Cell Line Tetracycline/pharmacology 03 medical and health sciences medicine Animals Cell Proliferation Transplantation Islet cell transplantation Cell growth lcsh:R Cell Biology Tetracycline Glucose 030104 developmental biology Gene Expression Regulation Cell culture Immunology Cancer research 030217 neurology & neurosurgery |
| Zdroj: | Cell Transplantation, Vol. 15, No 7 (2006) pp. 621-36 Cell Transplantation, Vol 15 (2006) |
| ISSN: | 1555-3892 0963-6897 |
| DOI: | 10.3727/000000006783981675 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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