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Digital archive of theses discussed at the University of Pisa


Thesis etd-03152012-084728

Thesis type
Tesi di dottorato di ricerca
Thesis title
Glycaemic control with Mesenchymal Stem Cells and Endothelial Progenitor Cells in an experimental model of pancreatic islet transplantation
Academic discipline
Course of study
tutor Prof.ssa Longoni, Bianca Maria
commissario Cremisi, Federico
commissario Paolicchi, Aldo
commissario Colantuoni, Antonio
  • Diabetes
  • Endothelial Progenitor Cells
  • Mesenchymal Stem Cells
  • pancreatic islet transplantation
Graduation session start date
Insulin-Dependent Diabetes Mellitus (IDDM or type 1) is an autoimmune, chronic disease characterised by hyperglycaemia, resulting from an inflammatory infiltration of the islets of Langerhans. The selective destruction of β-cells leads to a lower insulin secretion from the endocrine pancreas. The mainstay treatment for IDDM patients is chronic insulin injection. Although insulin therapy has dramatically reduced mortality from diabetes, patients often incur in complications such as nephropathy, neuropathy, angiopathy and retinopathy. Moreover, patients are risk severe and sometimes fatal hypoglycaemic events.
Pancreas transplantation is currently the only therapeutic approach to restore normoglycaemia and maintain long-term glucose homeostasis; moreover, this procedure improves patients’ quality of life.
An alternative to the replacement of the whole pancreas is the transplantation of islet of Langherans cells, isolated from donor pancreata and infused into the recipient’s liver via the portal vein.
Compared to solid organ transplantation, the advantages of islet transplantation consist in a relatively simple surgical procedure with low incidence of peri-operative risks. Nevertheless, the particular structure of pancreatic islets resulted in being injured after the isolation procedure.
However, the recurrence of immune response after transplantation and the diabetogenic and growth-stunting side effects of immunosuppressants are major challenges to the application of islet transplantation.
In the last decade many studies have demonstrated the efficacy of cell therapy either with Mesenchymal Stem Cells (MSCs) or Endothelial Progenitor Cells (EPCs) treatment when co-transplanted with pancreatic islets. The first type of cells were reported to modulate the immune response in an allogeneic transplant, preventing the graft-versus-host disease (GVHD) and also improving graft function in the long-term by maintaining glucose homeostasis. The EPCs showed to have strong revascularization properties in several diseases, such as cardiovascular disorders, atherosclerosis and diabetes.
This thesis aims to investigate the role of MSCs and EPCs in prolonging graft survival of pancreatic islet transplantation in a chemically induced rat model of type 1 diabetes in order to prolong the graft function and reach normoglycaemic levels in the long-term.
We used a rat model to investigate the effect of MSCs and EPCs in combination with islets of Langerhans (700 IE + 500,000 EPCs and 700 IE + 500,000 MSCs) in a syngeneic and an allogeneic diabetic-induced rat model which underwent pancreatic islet transplantation via the portal vein. These types of transplants were compared with islet alone treatment (700 IE), either syngeneic or allogeneic.
We obtained the reversal of the diabetic status in animals up to 6 months after the transplant when they had received islets and EPCs, and up to 75 days post transplant when they had received islets and MSC therapy. The glycaemic values were also confirmed by intraperitoneal glucose tolerance test measures for animals transplanted with IE and EPCs either in syngeneic or allogeneic models.
From data obtained from molecular biology assays on ex vivo liver tissues deriving from transplanted animals, we observed that a regulation in the revascularization and angiogenesis genes (VEGF-A, ANG-1, PECAM-1, SDF-1) occurred. Thus, EPCs could act through a regulatory mechanism as shown by their angiogenic gene expression.
These data suggested that both MSCs and EPCs were able to revascularize pancreatic islets and improve the syngeneic graft survival up to a complete healing in our diabetic animal model.