Investigating changes in beta cell function by modulating CD47

Abstract

Diabetes is a global health burden characterised by β-cell death and loss of function. Islet transplantation is a recognised treatment for patients with Type 1 Diabetes Mellitus (T1DM) and hypoglycaemic unawareness, but broader application is constrained by limited islet survival and function post transplantation.

CD47 is a cell surface protein implicated in cellular stress responses, but its role in β-cell function remains relatively unexplored.

The metabolic role for CD47 was characterised for the first time in β-cells. It was hypothesized that CD47 limits β-cell function and survival, and it was investigated whether CD47 signalling, or expression could be pharmacologically manipulated to enhance β-cell function and survival in the presence of various exogenous stressors, including hypoxia, hyperglycaemia, and endoplasmic reticulum (ER) stress, which are manifest in the peri-transplant period. CD47 inhibition via genetic deletion, silencing, or antibody blockade (in human islets and MIN6 β-cells) improved insulin protein expression. NOD mice treated with α-CD47 antibody had delayed development of hyperglycaemia. CD47-inhibited mouse islets compared to wildtype (WT, CD47+/+) mouse islets transplanted into diabetic mice significantly improved glucose control. Hypoxia increased CD47 expression while concurrently decreased insulin expression. CD47 inhibition under hypoxia increased insulin and pro-survival protein expression and limited senescence. CD47 inhibition protected MIN6 β-cells from ER stress by limiting the protein expression of ER stress markers (BiP, Ire1α and peif2a). Finally, CD47-silencing in MIN6 β-cells enhanced endothelial cell migration, via paracrine signalling.

Overall, this thesis provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction and inhibitor of cytoprotective responses to stress. Limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.