Regulated Cell Death Seen Through the Lens of Islet Transplantation

Clinical islet transplantation effectively restores euglycemia and corrects glycosylated hemoglobin in labile type 1 diabetes mellitus (T1DM). Despite marked improvements in islet transplantation outcomes, acute islet cell death remains a substantial obstacle that compromises long-term engraftment outcomes. Multiple organ donors are routinely required to achieve insulin independence. Therapeutic agents that ameliorate cell death and/or control injury-related inflammatory cascades offer potential to improve islet transplant success. Apoptotic cell death has been identified as a major contributor to cellular demise and therapeutic strategies that subvert initiation and consequences of apoptotic cell death have shown promise in pre-clinical models. Indeed, in numerous pathologies and diseases apoptosis has been the most extensively described form of regulated cell death. However, recent identification of novel, alternative regulated cell death pathways in other disease states and solid organ transplantation suggest that these additional pathways may also have substantial relevance in islet transplantation. These regulated, non-apoptotic cell death pathways exhibit distinct biochemical characteristics but have yet to be fully characterized within islet transplantation. We review herein the various regulated cell death pathways and highlight their relative potential contributions to islet viability, engraftment failure and islet dysfunction.