Bridging the gap to translation by understanding and preventing diabetic vascular complications using human organoids

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Diabetes is a major public health issue with current global prevalence estimated at 8.8% and rising due to the aging population and increasing obesity. The treatment of diabetes is putting a high strain on healthcare resources. 10% of the UK NHS budget is spent on treating diabetes, whilst in Canada the cost of new cases of diabetes diagnosed between 2012-22 is estimated at $15.4 billion. Many of these healthcare costs are due to treating complications associated with diabetes such as kidney disease, blindness, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in the vasculature, therefore, strategies which protect or repair blood vessels have the potential to be new therapies for diabetic patients. Studies using murine models and cultured cells have identified several candidate molecules which protect the diabetic vasculature. However, the challenge is to translate these findings into the clinical setting. For this, we need appropriate experimental models to bridge the gap between rodents and clinical trials.The research team on this proposal has made a key breakthrough in this area by developing vascular human organoids to model diabetes. Published in Nature (2019), these organoids are derived from human stem cells which are then exposed to a milieu of growth factors to assemble into capillary networks. Exposure of the organoid to high glucose or their transplantation into mice which are subsequently made diabetic leads to structural changes which mimic the changes to blood vessels seen in diabetic patients. Gene expression profiling has revealed molecular pathways altered in the blood vessels when the vascular organoid is exposed to hyperglycaemia. One of these is angiopoietin-2, which modulates blood vessel growth and inflammation and has been shown to drive vascular dysfunction in a murine model of diabetic kidney disease. The second is apelin, a peptide whose blockade has been shown to reduce tumor growth.This proposal will build on these findings by using the human vascular organoid to examine if blockade of angiopoietin-2 or apelin can prevent the hyperglycaemia induced changes in the human vessel organoid system (Aim 1). Secondly, we will use sophisticated animal models to work out how both angiopoietin-2 (Aim 2) and apelin (Aim 3) in blood vessels precisely effects diabetic vascular complications. Finally, we use the human vessel organoid system to understand why some patients are protected from diabetic vascular complications (Aim 4). To do this, we will use serum samples from type 1 diabetic patients with/without history of albuminuria (protected or susceptible towards the development of vascular disease in their kidneys), a general marker for blood vessel damage. We will expose the human vessel organoids to serum from these two groups of patients and examine changes in organoid structure, cellular composition and gene profile. Finally, we will use non-biased proteomics to assess the composition of the serum to identify protective factors which prevent blood vessel damage in diabetes.Collectively, our proposal will bridge the gap between rodent studies and clinical trials and test the potential of manipulating angiopoietins and apelin as a therapy for diabetic vascular complications. We predict that using samples from diabetic patients with/without albuminuria will facilitate the discovery of new therapeutic targets to treat diabetic complications in the future.