Aortic aneurysms kill thousands of people each year, yet researchers still rely on animal experiments to study how these blood vessel bulges form. This project builds a better alternative: three-dimensional human tissue models grown in a dish from stem cells carrying the same genetic mutations that cause aneurysms in patients. The problem is that existing lab models fall short. Cells grown flat on plastic dishes do not mimic the complex structure of real blood vessels, and primary human smooth muscle cells quickly lose their identity in culture. The engineered vascular tissues (EVTs) developed here retain the extracellular matrix that smooth muscle cells naturally secrete, creating a more realistic environment. By combining these tissues with detailed proteomic analysis, the team can directly compare the matrix composition of their lab-grown tissues against actual human aneurysm tissue. If validated, this model could replace thousands of animal experiments each year. More importantly, it would allow researchers to link specific genetic mutations to the molecular mechanisms driving aneurysm formation, and to test new drugs on human tissue rather than on mice. The work is applied rather than fundamental science—the goal is a validated tool ready for immediate use in vascular disease research.
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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.
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