Influence of human allogenic bone marrow and cord blood-derived mesenchymal stem cell secreting trophic factors on ATP (adenosine-5'-triphosphate)/ADP (adenosine-5'-diphosphate) ratio and insulin secretory function of isolated human islets from cadaveric donor.

Successful islet transplantation (ITx) is not only dependent on the number of islets, but also their quality, including viability, metabolic activity, and function. Islet quality decreases during cultivation after the isolation procedure. To overcome this obstacle, we established the practice of islet and mesenchymal stem cells (MSCs) coculture. This coculture condition improved the ATP (adenosine-5'-triphosphate)/ADP (adenosine-5'-diphosphate) ratio and insulin secretory function in vitro. It is believed that the enhancement of islet quality in islet-MSCs cocultures may be caused by the secretion of active agents by MSCs. Herein we have shown that interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-beta) were significantly increased as measured by enzyme-linked immunosorbent assay (ELISA) in MSCs-cultured medium, factors that have been shown to improve the survival, function, and angiogenesis/revascularization of islets. These results indicated that the quality of human islets was enhanced by trophic molecules secreted by MSCs, which influence the intracellular islet ATP content and insulin secretory function.

Healthy twin birth after autologous islet transplantation in a pancreatectomized patient due to a benign tumor.

OBJECTIVE: Autologous islet transplantation has been reported to show favorable outcomes on glucose metabolism. The objective of this study was to describe successful delivery of twins in an islet recipient who had undergone distal pancreatectomy. PATIENT: A 35-year-old woman who underwent distal pancreatectomy owing to a solid pseudopapillary neoplasm received an autologous islet transplantation (140,000 islet equivalents). After 2.5 years, she unexpectedly became pregnant. Cesarean section was performed at 35 weeks delivering male twins without complications. Plasma glucose and insulin levels, insulinogenic index, and hemoglobin A1c were measured from the preoperative to the postpartum state as the main outcome. RESULTS: The patient showed impaired glucose tolerance before pancreatectomy, but improved to a normal glucose tolerance after transplantation, maintaining euglycemia until pregnancy. Because her fasting glucose levels were within the normal range during pregnancy, fasting insulin represented insulin resistance. Her fasting insulin levels abruptly increased in the third trimester of pregnancy, but returned after delivery. Insulinogenic index increased over 1 year after transplantation, but gradually decreased thereafter. During pregnancy, it increased again, but could not compensate for the insulin resistance. Therefore, gestational diabetes mellitus developed: glucose homeostasis recovered to normal after delivery. CONCLUSIONS: The current report suggested a successful pregnancy after autologous islet transplantation that did not itself permanently deteriorate graft function.

A more persistent tolerance to islet allografts through bone marrow transplantation in minimal nonmyeloablative conditioning therapy.

INTRODUCTION: Islet transplantation is a therapeutic approach to prevent diabetes complications. However, the side effects of the required lifelong immunosuppressive regimens to prevent graft rejection restrict the impact of type 1 diabetes. One strategy to overcome these limitations is tolerance induction and graft acceptance through hematopoietic chimerism. In this study we investigated whether tolerance to major histocompatibility complex (MHC) and minor-disparate islet allografts could be induced by minimal nonmyeloablative conditioning and whether more persistent donor-specific islet allografts were accepted if the grafts were implanted with simultaneous bone marrow cells. METHODS: The donor and recipient mice were BALB/c(H-2(b)) and C57BL/6(H-2(d)), respectively. In group 1 streptozotocin-induced diabetic C57BL/6(H-2(d)) mice received only 500 islets of BALB/c(H-2(b)). Group 2 recipients conditioned with antilymphocyte serum, 100 cGy total body irradiation and cyclophosphamide were given islet cells of BALB/c(H-2(b)), but group 3 were simultaneously given 30 x 10(6) BALB/c(H-2(b)) mice BMCs and islet cells similar to group 2. RESULTS: We obtained 5% to 6% allogeneic donor chimerism and 60% graft survival at 80 days after islet transplantation in group 3. We observed lymphocyte infiltration around the islet without destruction of endocrine cells and the presence of strong insulin/glucagon-stained cells in group 3. CONCLUSION: This minimal nonmyeloablative conditioning therapy induced donor chimerism and immune tolerance between MHC- and minor-disparate (BALB/c-->C57BL/6) mice and long-term islet graft survival was obtained through cotransplantation of bone marrow cells.