Background Pre‐transplant modification of porcine islets may improve their suitability for clinical use in diabetes management by supporting graft function and reducing the potential for xeno‐rejection. The present study investigates intra‐graft incorporation of stem cells that secrete beta (β)‐cell trophic and immunomodulatory factors to preserve function and alter immune cell responsiveness to porcine islets. Methods Isolated porcine islets were maintained in a three‐dimensional rotational cell culture system (RCCS) to facilitate aggregation with human amniotic epithelial cells (AECs). Assembled islet constructs were assessed for functional integrity and ability to avoid xeno‐recognition by CD4+ T‐cells using mixed islet:lymphocyte reaction assays. To determine whether stem cell‐mediated modification of porcine islets provided a survival advantage over native islets, structural integrity was examined in a pig‐to‐mouse islet transplant model. Results Rotational cell culture system supported the formation of porcine islet:AEC aggregates with improved insulin‐secretory capacity compared to unmodified islets, whilst the xeno‐response of purified CD4+ T‐cells to AEC‐bearing grafts was significantly (P < 0.05) attenuated. Transplanted AEC‐bearing grafts demonstrated slower rejection in immune‐competent recipients compared to unmodified islets. Conclusions/interpretation Rotational culture enables pre‐transplant modification of porcine islets by integration with immunomodulatory stem cells capable of subduing xeno‐reactivity to CD4+ T‐cells. This reduces islet rejection and offers translational potential to widen availability and improve the clinical effectiveness of islet transplantation.

Pancreatic islet cell transplantation has proven efficacy as a treatment for type 1 diabetes mellitus, chiefly in individuals who are refractory to conventional insulin replacement therapy. At present its clinical use is restricted, firstly by the limited access to suitable donor organs but also due to factors associated with the current clinical transplant procedure which inadvertently impair the long‐term functionality of the islet graft. Of note, the physical, biochemical, inflammatory, and immunological stresses to which islets are subjected, either during pretransplant processing or following implantation are detrimental to their sustained viability, necessitating repeated islet infusions to attain adequate glucose control. Progressive decline in functional beta (β)‐cell mass leads to graft failure and the eventual re‐instatement of exogenous insulin treatment. Strategies which protect and/or preserve optimal islet function in the peri‐transplant period would improve clinical outcomes. Human amniotic epithelial cells (HAEC) exhibit both pluripotency and immune‐privilege and are ideally suited for use in replacement and regenerative therapies. The HAEC secretome exhibits trophic, anti‐inflammatory, and immunomodulatory properties of relevance to islet graft survival. Facilitated by β‐cell supportive 3D cell culture systems, HAEC may be integrated with islets bringing them into close spatial arrangement where they may exert paracrine influences that support β‐cell function, reduce hypoxia‐induced islet injury, and alter islet alloreactivity. The present review details the potential of multifunctional HAEC in the context of islet transplantation, with a focus on the innate capabilities that may counter adverse events associated with the current clinical transplant protocol to achieve long‐term islet graft function.