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.

Keywords: biomaterials; diabetes; islet transplantation; stem cells; vascularization.

Figure 1

Islet transplantation sites that have been tested in mouse models and higher mammalian models. The three major factors contribute to success of islet transplantation are the 1. Presence of vascularization and innervation, 2. Immune-modulating factors which affect innate inflammatory response and graft rejection, 3. Accessibility for surgical procedure and absence of major surgical complications. Each transplantation site shows advantages and disadvantages which have been explored. While intra-hepatic infusion is the only clinically applied site for islet transplantation, there are extra-hepatic candidate sites that may superior islet transplantation site. The anterior chamber of the eye is highly vascularized innervated and immune-privileged in most conditions low and atypical expression of MHC class I and II, as well as presence of anti-inflammatory and immune-modulating factors in the intra-ocular fluid is beneficial for islet engraftment. Subcutaneous space is not immune-privileged and poorly vascularized but ease of access and simplicity of surgical procedure and complications makes it an attractive site for islet transplantation. Liver via hepatic portal infusion is the only clinically approved site of transplantation due to success of Edmonton protocol, but extensive loss of islet necessitates for multiple islet donors. Hepatic micro-environment is considered a factor in long-term decline of viability of transplanted islets. Spleen is highly vascularized and drains into the hepatic portal vein and may contain immune-modulating Tregs. Omentum or epididymal fat (murine equivalent) is highly vascularized, and potentially-immune privileged. It can accommodate large islet volume, including a different immuno-modulating co-transplanted cells and biomaterials and devices. Kidney capsule is routinely used as site for islet transplantation in murine subjects, but clinical translation to humans is limited due to common diabetes-related renal complications. Bone marrow is highly vascularized but requires pre-conditioning before it can be considered for islet transplantation.

Figure 2

Major immune components in each site affecting success of transplantation. Each islet transplantation sites have different microenvironment, which include immune system components that either increase or decrease of islet engraftment. Some of these sites, such as the omentum, spleen and anterior chamber of the eye, are considered immune-privileged. The presence of anti-inflammatory factors and regulatory T-cells that suppress expansion of effector T-cells and decreasing the effects of proinflammatory cytokines are key immune modulators in immune privilege sites. Other sites, such as the subcutaneous space and the bone marrow sites contain T cells and NK cells, among other immune cells that contribute to graft rejection and long-term viability of transplanted islets. Strategies must be incorporated in these sites to not only increase angiogenesis but also modulate immune responses to prevent graft rejection. The potential anti-inflammatory components in each site are described by blue color and the potential inflammatory components in each site are described by red color.