Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

Abstract

Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.

Emerging strategies for beta cell transplantation to treat diabetes

“…Recent advances in reduction of capsule thickness through conformal coating have made intraportal delivery feasible [37]; however, transplant retrievability remains an issue. Other implantation sites recently explored include epididymal fat pad, skeletal muscle, and subcutaneous (SQ) tissue [38,39]. Although preclinical studies in rodents have demonstrated efficacy, transplantation of a clinically relevant mass within these alternate sites remains an obstacle for translation.…”

Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells

“…Subcutaneous transplantation is easy to operate with minimally invasive delivery and few surgical complications and is accessible to monitor and retrieve the grafts, but there is low vascular density. Other more vascularized and/or immune-privileged sites also have limitations; for instance, the omentum needs an invasive operation, and the anterior chamber of the eye is only suitable for blind patients (Cayabyab et al, 2021 ). Ideally, transplanting unencapsulated or minimally physiologically impaired, robustly functional human PSC-derived β cells without compromising the immune system of the recipient is optimal for the PSC-based islet replacement therapy, which needs constant effort.…”

The Influence of Microenvironment on Survival of Intraportal Transplanted Islets

“…During transplantation, islet grafts are damaged by multiple challenges, including enzyme and mechanical damage caused by the isolation process, hypoxia, inflammation, immune rejection and toxicity of immunosuppressive drugs ( 8 ). The liver is currently the preferred transplantation site because the procedure is minimally invasive, easy to perform, and has low rates of bleeding and thrombosis ( 9 ). Early inflammatory responses strongly influence islet engraftment and survival after intrahepatic transplantation.…”