Improving beta cell function by mesenchymal stromal cells: novel mechanisms and cell-free translational potential

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Islet transplantation offers the prospect of a cure for type 1 diabetes (T1D) rather than merely treating the symptoms with insulin. However, a major problem with islet transplantation as a treatment is the significant loss of graft function (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. In experimental animals 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. We are therefore studying how MSCs improve islet graft survival and function to replicate the beneficial effects of MSCs in an "MSC-free" system. We have previously shown that some of the beneficial effects of MSCs can be attributed to biologically active molecules which they secrete and can be replicated merely by supplying the molecules to the islets before transplantation. In this project we plan to look at two other mechanisms through which MSCs may influence islet function. First, like many other cell types, MSC release small, membrane bound vesicles ("extracellular vesicles"; EVs) to communicate with other cells by transporting biologically active molecules and other cellular components. We will assess whether treating islets with MSC-derived EVs has beneficial effects on their functional survival and thus on the outcomes of islet transplantation. Second, we have recently reported that MSCs can transfer some of their mitochondria - subcellular organelles which are vital for normal cell function - to functionally-compromised islet cells. We will investigate how mitochondria are transferred between MSCs and islet cells, and whether this is associated with improved islet function. Information gained from this project will 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 graft recipients.