Joint NC3Rs/BHF PhD Studentship: Using a novel human 3D spheroid model to study mechanisms and therapeutics for vascular calcification

Vascular calcification (VC) is a serious and widespread clinical problem manifesting in atherosclerosis, chronic kidney disease (CKD), diabetes and ageing. Currently, there are no treatments to prevent or regress VC. VC is a cell-mediated process, driven by vascular smooth muscle cells (VSMCs). Signalling pathways activated in response to stressors cause VSMCs to undergo phenotypic change and conversion to osteogenic-like cells capable of orchestrating the calcification process. The development of VC is also highly dependent on the extracellular matrix (ECM) environment surrounding the VSMCs. Current mechanistic and preclinical research into VC relies predominantly on 2D in vitro models of rodent VSMCs grown in the absence of ECM. Our aim is to replace animal use with human models of VC. To this end we have developed two novel human 3D in vitro models of VC; a spheroid model and a modified ECM model. Here, VSMC osteogenic differentiation and mineralisation occurs without the need for additional stimuli and in the context of the native ECM. We propose to characterise and refine these models to determine mechanisms calcification and to optimise them for use in high throughput screening (HTS) to identify drugs that inhibit calcification processes.