Studying vesicles released by pancreatic islets before transplantation in type 1 diabetes

The greatest limitation and challenge of islet transplantation lies in the substantial loss of islet mass infused via the portal vein at the start of the post-transplant period. Up to 50 per cent of the graft may be lost in the days following transplantation. This early loss is due to a combination of stress and non-specific inflammatory and immune mechanisms, as well as blood-mediated inflammatory reactions, which compromise the survival, engraftment, revascularisation and early function of the transplanted islets. Consequently, multiple islet infusions are often required to achieve satisfactory metabolic outcomes in recipients. However, due to the scarcity of available donors, the widespread application of islet transplantation remains limited as a result. During the culture period, cells in the islet preparation release extracellular vesicles (EVs) - either secreted by the plasma membrane (microvesicles, MVs) or of intracellular endosomal origin (exosomes) - which play a major role in intercellular communication. Microvesicles carry various markers and effectors that can render them either harmful (pro-coagulant, pro-apoptotic, pro-inflammatory and pro-senescent) or protective. We therefore hypothesise that (1) EVs released during the preparation of islets prior to transplantation (hereinafter referred to as Graft-EVs) reflect the quality of the pancreatic islets, (2) certain EVs have a protective or deleterious effect on the pancreatic islet, and (3) reconditioning the islets by enriching them with protective EVs improved graft quality under the pro-inflammatory conditions of IBMIR.

We therefore propose to develop an EV-based islet preconditioning strategy to improve graft survival and function.