Heterogenous expression of endocrine and progenitor cells within the neonatal porcine pancreatic lobes-Implications for neonatal porcine islet xenotransplantation.

Neonatal porcine islets (NPIs) are a source of islets for xenotransplantation. In the pig, the pancreatic lobes remain separate, thus, when optimizing NPI isolation, the pancreatic lobes included in the pancreatic digest should be specified. These lobes are the duodenal (DL), splenic (SL) and connecting (CL) lobe that correspond to the head, body-tail, and uncinate process of the human pancreas. In this study we are the first to evaluate all three neonatal porcine pancreatic lobes and NPIs isolated from these lobes. We report, a significant difference in endocrine and progenitor cell composition between lobes, and observed pancreatic duct glands (PDG) within the mesenchyme surrounding exocrine ducts in the DL and CL. Following in vitro differentiation, NPIs isolated from each lobe differed significantly in the percent increase of endocrine cells and final cell composition. Compared to other recipients, diabetic immunodeficient mice transplanted with NPIs isolated from the SL demonstrated euglycemic control as early as 4 weeks (p < 0.05) and achieved normoglycemia by 6 weeks post-transplant (p < 0.01). For the first time we report significant differences between the neonatal porcine pancreatic lobes and demonstrate that NPIs from these lobes differ in xenograft function.

Fibrin supports subcutaneous neonatal porcine islet transplantation without the need for pre-vascularization.

BACKGROUND: Neonatal porcine islets (NPIs) are a promising tissue source for clinical islet xenotransplantation. To facilitate graft monitoring and recovery if needed, an extra-hepatic transplant site would be optimal. In addition, islet transplantation into the portal vein has been associated with life-threatening intraperitoneal bleeding, portal vein thrombosis, hepatic steatosis, and loss of islet graft function. Although it is hypoxic, the subcutaneous space is a potential extra-hepatic location for clinical islet transplantation. In this study, we explore the benefits of fibrin scaffolds in enhancing the engraftment and long-term function of NPI grafts in this ectopic site. METHODS: Diabetic immune-compromised mice were transplanted with 5000 NPIs under the kidney capsule (KC), and subcutaneously with or without fibrin (SC + F, SC, respectively). All mice were monitored for reversal of hyperglycemia and long-term metabolic function. RESULTS: All mice transplanted with NPI under the KC or SC + F (12/12 and 17/17, respectively) achieved normal fasting blood glucose levels between 5 and 22 weeks post-transplantation and displayed normal glucose tolerance during an intraperitoneal glucose tolerance test. In contrast, NPIs transplanted SC with no fibrin (n = 7) failed to obtain normoglycemia. CONCLUSION: Fibrin matrix facilitates engraftment of NPIs in the subcutaneous site of diabetic mice. These data support further investigation of the subcutaneous site for clinical islet xenotransplantation.

Porcine Islet Xenografts: a Clinical Source of ß-Cell Grafts.

PURPOSE OF REVIEW: Diabetes is medical and social burden affecting millions around the world. Despite intensive therapy, insulin fails to maintain adequate glucose homeostasis and often results in episodes of hypoglycemic unawareness. Islet transplantation is a propitious replacement therapy, and incremental improvements in islet isolation and immunosuppressive drugs have made this procedure a feasible option. Shortage of donors, graft loss, and toxic immunosuppressive agents are few of many hurdles against making human allogenic islet transplantation a routine procedure. RECENT FINDINGS: Xenografts-especially pig islets-offer a logical alternative source for islets. Current preclinical studies have revealed problems such as optimal islet source, zoonosis, and immune rejection. These issues are slowing clinical application. Genetically modified pigs, encapsulation devices, and new immune-suppressive regimens can confer graft protection. In addition, extrahepatic transplant sites are showing promising results. Notwithstanding few approved clinical human trials, and available data from non-human primates, recent reports indicate that porcine islets are closer to be the promising solution to cure diabetes.