Sex Differences in Maturation and Function of Neonatal Porcine Islets Upon Transplantation in Mice

Abstract

Background: Neonatal porcine islets (NPIs) can mature into a mixed population of endocrine cells that can restore glucose control in mice, pigs, and non-human primates, representing a potential alternative islet source for clinical beta cell replacement therapy. However, it remains unclear how conditions in the recipient influence the maturation and function of these cells. Here, we investigated the impact of host sex on NPIs implanted under the kidney capsule of male and female B6.129S7-Rag1tm1Mom (B6/Rag−/−) mice. Methods: Diabetic mice were transplanted with 3000 NPIs under the kidney capsule. All mice were monitored for reversal of hyperglycemia and glucose clearance at 8- and 20-weeks post-transplant. Grafts were assessed for cell composition and insulin content. Results: Female mice demonstrated improved glucose clearance at 8- and 20-weeks post-transplant compared to their male counterparts. Improved glucose clearance correlated with accelerated diabetes reversal in females (8 weeks vs. 12 weeks in males) and increased rates of euglycemic achievement (17/18 in females vs. 14/19 in males). However, grafts collected from male mice exhibited an increased percentage of insulin-positive cells as well as increased insulin content. Conclusion: The sex of the host influences the outcomes of NPI transplantation, showcasing the relevance of understanding the role of sex as a biological variable in islet transplantation.