Introduction: Despite the remarkable progress made over the past decades and important clinical results in transplanting autologous pancreatic islets, clinical islet transplantation remains suboptimal in terms of engraftment and long-term survival. Islet transplantation is hampered by difficulties to reach sufficient mass to ensure insulin independence, caused by primary non-function against donor islets. An aggressive immune suppressive regime is typically life-long administered to the recipient to prevent rejection of the transplanted allogenic mass, with related side effects. Perinatal stem cells, a next generation of regenerative medicine provides alternative approaches to prevent such systemic immune suppression regimens. Perinatal AECs are naturally equipped with trophic, anti-inflammatory, angiogenic, and immune-modulatory components that modulate rather than suppress immune protection.

Methods: We combine the immuno-modulatory and regenerative properties offered by perinatal amnion epithelial cells (AEC) with the (allo)transplantation of pancreatic islets. We implanted xeno-ISLÆTS into the anterior chamber of the eye and evaluated the survival and phenotype of the graft in streptozotocin-treated, immune-competent mice. We profiled surface molecules (FACS) and secreted mediators (Luminex) in several AEC donors, and measured their effects in vivo, on the murine immune system.

Results: We generated hybrid cellular organoids (ISLÆTS) composed of primary pancreatic islets and human AEC. Preclinical studies supported superior engineered islets characterized by long-term allograft acceptance (>200 days) without administration of immunosuppressive. We observed AEC to induce Treg and Breg cell generation. We profiled AEC surface molecules (such as HLA-1b, ectonucleotidases) as well as soluble mediators (including VEGF, IL-2, Tweak, M-CSF) responsible for angiogenesis and immune cell requalification, promoting (local or systemic) tolerance.

Conclusion: Adjunct strategies based on angiogenic, trophic, and immuno-modulatory perinatal stem cells, rather than immune suppression, could improve current islet transplantation protocols, abetting normal immune response towards eventual infective agents and extending cellular therapies to patients commonly not considered for risks of side effects (e.g., pediatric). Our therapeutic paradigms are applicable to both type 1 and 2 diabetes, and potentially expanded to a variety of auto-immune disease states. The successful implementation of this strategy will likely enhance therapeutic approaches applicable to both diabetes and autoimmune disorders.