Role of Thrombospondin-1 in Endogenous and Transplanted Pancreatic Islets

Sammanfattning: Type 1 diabetes mellitus is a severe life-long disease with a pronounced risk of developing secondary complications. One way to avoid the latter is to restore the fine tuning of blood glucose homeostasis by transplantation of pancreatic islets. However, isolated islets need to be properly engrafted and to re-establish a vascular network in order to regain function. Earlier studies have shown that pancreatic islets experimentally transplanted to e.g. the liver or the kidney become poorly revascularized.In the present thesis, mice deficient of the angiostatic factor thrombospondin-1 (TSP-1) were found to have an impaired beta-cell function. Development of this beta-cell dysfunction was prevented by treatment of TSP-1 deficient mice from birth with the TGFbeta-1 activating sequence of TSP-1. TSP-1 in islets was predominantly expressed in the endothelial cells.Isolated islet endothelial cells was observed to have a low proliferatory and migratory capacity towards angiogenic stimuli, but this could be reversed by neutralizing antibodies to the angiostatic factors alpha1-antitrypsin, endostatin or TSP-1. Transient downregulation of TSP-1 expression in mouse islet cells prior to transplantation improved graft revascularization, blood perfusion, oxygenation and function when evaluated one-month post-transplantation. The same result was achieved when islets or recipients of islets were pre-treated with the hormone prolactin one-month post-transplantation.The present study illustrates the importance of the angiostatic factor TSP-1 for islet beta-cell function and engraftment of islets following transplantation. Interference with TSP-1 can possibly be used to improve the results of clinical islet transplantation.