Recent advances provide evidence that the cellular signalling pathway comprising the ligand-receptor duo of thrombospondin-1 (TSP1) and CD47 is involved in mediating a range of diseases affecting renal, vascular, and metabolic function, as well as cancer. In several instances, research has barely progressed past pre-clinical animal models of disease and early phase 1 clinical trials, while for cancers, anti-CD47 therapy has emerged from phase 2 clinical trials in humans as a crucial adjuvant therapeutic agent. This has important implications for interventions that seek to capitalize on targeting this pathway in diseases where TSP1 and/or CD47 play a role. Despite substantial progress made in our understanding of this pathway in malignant and cardiovascular disease, knowledge and translational gaps remain regarding the role of this pathway in kidney and metabolic diseases, limiting identification of putative drug targets and development of effective treatments. This review considers recent advances reported in the field of TSP1-CD47 signalling, focusing on several aspects including enzymatic production, receptor function, interacting partners, localization of signalling, matrix-cellular and cell-to-cell cross talk. The potential impact that these newly described mechanisms have on health, with a particular focus on renal and metabolic disease, is also discussed.

Diabetes is a global public health burden and is characterized clinically by a relative or absolute insulin deficiency. Therapeutic agents that stimulate and improve insulin secretion and insulin sensitivity are in high demand as diabetic treatment. CD47 is a cell surface glycoprotein implicated in multiple cellular functions, including recognition of self, angiogenesis, and nitric oxide signaling, however its role in the regulation of insulin secretion remains unknown. For the first time we demonstrate that CD47 receptor signaling inhibits insulin release from β-cells and that it can be pharmacologically exploited to boost insulin secretion. CD47 depletion stimulates insulin granule exocytosis via activation of the Rho GTPase Cdc42. CD47 deficiency improved glucose clearance and insulin sensitivity in mice. CD47 blockade enhanced islet transplantation efficiency and improved outcomes. Further, anti-CD47 antibody treatment delayed the onset of diabetes in non-obese diabetic mice and protected them from overt diabetes. Our findings identify CD47 as a previously unrecognized regulator of insulin secretion and its manipulation in β-cells offers a novel therapeutic opportunity for diabetes and islet transplantation by correcting insulin deficiency.

Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.

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