Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function

Sammanfattning: The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it.   As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.