Decoding extracellular matrix protein heterogeneity in cardiac fibrosis using 3D cardiac organoids

Cardiac fibrosis is a common feature observed in heart failure patients. Fibrosis is often defined as the excessive production of extracellular matrix (ECM) proteins, which negatively impact the ability of the heart to contract and relax. As fibrosis is so common in heart failure patients, it is a promising target for therapies. However, development of antifibrotic treatments is a huge challenge as we do not fully understand the signalling pathways that drive fibrosis. One of the main goals of the Cardiac Drug Discovery laboratory is to improve our understanding of what exactly fibrosis is and how it develops. Using human cardiac organoids – a live contracting 3D model incorporating many important heart cell types, including cardiomyocytes and fibroblasts – we have established a model for cardiac fibrosis. By treating these organoids with profibrotic mediators, we can study how this impacts gene and protein expression, signalling and importantly, cardiac function. This work has led us to discover that different profibrotic stimuli lead to different functional and ECM changes, highlighting that fibrosis is highly heterogeneous.

This project aims to further tease apart how cardiac dysfunction and ECM changes are interconnected.

This project involves laboratory experiments using profibrotic stimuli on human cardiac organoids (hCOs), together with functional analysis, immunohistochemistry, microscopy (light, fluorescence and confocal) and mass spectrometry-based proteomics.

This project will improve our understanding of the fundamental mechanisms that are involved in the development of cardiac fibrosis, which may have major implications for antifibrotic treatment strategies.