Impact of Exendin-4 on the Differentiation and Function of Transplanted Porcine Neonatal Pancreatic Cell Clusters in Diabetic Nude Mice.

Porcine neonatal pancreatic cell clusters (NPCCs) are a promising and abundant source for islet transplantation owing to their ability to secrete insulin and proliferative potential. However, a significant limitation is the delayed normalization of blood glucose following transplantation, largely attributed to incomplete β-cell differentiation. Exendin-4, a glucagon-like peptide-1 receptor agonist, has been shown to enhance β-cell differentiation, proliferation, and function in various models. This study was aimed at investigating whether posttransplant treatment with exendin-4 could accelerate NPCC differentiation and improve long-term glycemic outcomes in diabetic nude mice. NPCCs were isolated from 1- to 3-day-old piglets and transplanted under the kidney capsule of streptozotocin-induced diabetic nude mice. Recipients received subcutaneous injection of either exendin-4 (3 μg/kg) or saline (as control) twice daily. Graft differentiation was assessed at Days 6, 9, and 16 via immunostaining for insulin, glucagon, PDX1, and SOX9. Blood glucose levels, body weight, and graft histology were monitored over time. Exendin-4 treatment significantly increased the proportion of mature insulin+ cells at Day 9 (p < 0.05) and both PDX1+/insulin- and SOX9+ progenitor cells at Day 6 (p < 0.01). By Week 10, hyperglycemia persisted in both groups; however, exendin-4-treated recipients exhibited a significant reduction in blood glucose from Week 6 onward. At this time point, grafts from hyperglycemic mice displayed both insulin-/PDX1+ (progenitor cells) and insulin+/PDX1+ (mature) β-cells, indicating ongoing differentiation. Among mice maintained beyond 10 weeks, euglycemia was achieved between Days 119 and 308, with grafts exhibiting mature insulin+/PDX1+ cells-evidence of morphological and functional maturation. Our results indicate that exendin-4 transiently enhances NPCC differentiation and expands the progenitor population in early posttransplantation phases. Furthermore, it contributes to improved graft performance and glycemic control, likely through its well-established metabolic effects.