Accelerate adoption of engineered vascular tissues with induced pluripotent stem cell-derived smooth muscle cells

Manuel’s award will support the transfer of the engineered vascular tissue model developed during his joint BHF-NC3Rs PhD studentship to the lab of Professor Sanjay Sinha at the University of Cambridge for use in the study of aortic aneurysmal disease. The project will expand the applicability of the model by incorporating induced pluripotent stem cell-derived human vascular smooth muscle cells with defined mutations of aortic and vascular diseases, a technology pioneered by the Sinha lab and used to study genetic predispositions to vascular disease. The suitability of the model for replacing the use of mice in the Sinha lab for investigating mechanistic links between specific mutations and aneurysm formation will be evaluated using proteomic analyses of the extracellular matrix and benchmarking studies against human aneurysmal tissue samples. 

The project aims to advance the adoption of engineered vascular tissues (EVTs) as a novel in vitro model, integrating this approach into the research conducted in Professor Sanjay Sinha's laboratory. Professor Sinha, a leading expert in the use of induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells (SMCs), and his team will utilise iPSC-derived SMCs with mutations predisposing patients to aortic aneurysmal disease in EVTs. The key objective is to assess the suitability of the EVT model for linking genetic mutations to mechanisms of aneurysm formation by combining iPSC-derived SMCs with a detailed proteomic analysis of the extracellular matrix (ECM) within these three-dimensional tissues.

ECM remodelling is a hallmark of many vascular diseases, particularly aneurysm formation - a condition associated with ECM degradation and remodelling. iPSC-derived SMCs enable the study of defined pathogenic mutations, whereas primary SMCs are limited by their proliferative capacity and are prone to phenotypic changes and senescence in culture. The ECM profiles of EVTs created from iPSC derived SMCs will be compared to those of human aneurysmal tissues. Unlike conventional two-dimensional cultures, EVTs retain the newly secreted SMC ECM, offering a more pathophysiologically relevant model.

This collaboration between Professor Sinha’s and Professor Mayr’s laboratories will provide thorough characterisation and validation of the EVT model by incorporating iPSC-derived SMCs into EVTs and comparing their ECM profiles to actual human aneurysmal tissues. This approach offers a significant advancement by providing more accurate and relevant research outcomes in vascular disease studies. Ultimately, developing an accurate in vitro human 3D model of aortic aneurysm disease using EVTs will reduce the need for thousands of animal experiments each year and yield better scientific outcomes by
enabling the dissection of human disease pathology and the screening and testing of new therapeutics.