Using mesenchymal stromal cell secretory products to improve human islet transplantation.

Islet transplantation offers the prospect of a cure for type 1 diabetes (T1D) rather than merely treating the symptoms with insulin, which should bring major benefits in reducing the secondary complications associated with T1D. Islet transplantation is currently reserved as a treatment for a subgroup of patients with T1D who fail to improve their hypoglycaemia despite state-of-the-art medical therapy. A major problem with islet transplantation as a treatment is the significant loss of transplanted cells (up to 80%) which occurs in the 24-48 hours immediately after transplantation. This loss of function is partly because the isolated islets in the graft are fragile and easily damaged, and partly because the graft environment, inside the liver bloodstream, reacts to the graft by causing inflammation which irreversibly damages the islets. As a result, insulin independence is only achieved long-term in 17% of UK's islet cell transplant recipients. In animal studies, co-transplanting "helper" cells known as mesenchymal stromal cells (MSCs) with islets improves graft function and survival, and suppresses inflammation, but this is not technically feasible in clinical human islet transplants. KCL islet biology group has experimental evidence from studies using mouse models of islet isolation, treatment and transplantation suggesting that many of the beneficial effects of MSCs can be attributed to biologically active molecules which they secrete and that the benefits can be replicated merely by supplying the molecules to the islets before transplantation. I will now investigate how to use such molecules to improve islet graft survival and function in -cell-free" system, with the aim of using this information to improve outcomes of clinical protocols for human islet transplantation.

This project will demonstrate the translational potential of this approach by assessing whether pre-treatment of isolated human islets with MSC-derived molecules is able to protect them during the period immediately after transplantation, to improve the long-term chances of graft survival and function. I will assess human islet function and survival under experimental conditions designed to mimic the post-transplantation environment and use this information to inform a study in a recently developed mouse model of human islet transplantation. During these studies I will also investigate new blood tests or biomarkers that could tell us how well the islet cells are functioning in transplant recipients. In parallel, I will liaise with the UK Islet Transplantation Consortium (UKITC), the clinical consortium of human islet transplantation centres within the UK, to design a first-in-man clinical study to assess the benefits of pre-treating human islets with MSC-derived molecules before transplantation. Our collaboration with the UKITC, which has an established infrastructure for conducting research and delivering pioneering work in islet cell transplantation, will ensure the fastest route to translation of our experimental studies to improve the outcomes of this treatment.

This project will therefore inform how best to design "cell-free" treatments of human islets prior to transplantation to improve the functional survival of the islet graft, particularly within the first few days after transplantation, and so improve the clinical outcomes for individual islet transplant recipients.

Allogeneic islet transplantation is currently used to treat a subgroup of patients with type 1 diabetes (T1D). Current clinical protocols are inefficient with up to 80% loss of transplanted cells within 48-72 hours after transplantation. Mesenchymal stromal cells (MSCs) improve islet function but current clinical transplantation protocols do not enable co-transplantation of islets with MSCs. I will be focusing on harnessing the beneficial effects of MSCs in "cell-free" protocols. The KCL Islet biology group have demonstrated that some of the effects of MSCs on islet function are mediated by soluble mediators acting via G-protein coupled receptors and that pre-treatment of rodent islets with cocktails of MSC-derived molecules improves functional survival of islets in mouse models of T1D. I will investigate the translational potential of these observations to human islet transplantation by first assessing the effects of MSC-derived secretory factors on human islet survival and function in vitro under experimental conditions which mimic the hypoxic, inflammatory conditions experienced by human islet grafts in the immediate post-transplantation period. I will then define an optimal treatment regimen with a cocktail of MSC-derived factors to improve human islet function and survival. Using whole blood exosomes and cell-free DNA, I will also investigate putative biomarkers for transplanted human islet cell function and death that can be used to understand the mechanism of action of the MSC-derived factors. Secondly, I will assess the effects of pre-treatment on the functional survival of human islet grafts in vivo in a newly developed mouse model of human islet transplantation using remote continuous glucose monitoring to detect changes in glycaemic control. Finally, I will work closely with the UK Islet Transplantation Consortium (UKITC) to design and prepare for a first-in-man clinical study to assess the benefits of pre-treating human islets before transplantation.