Repair & Regeneration

Overview

This theme extends beyond regenerative medicine as applied to acute myocardial infarction (MI) and heart failure (HF), to other disease indications in which repair and regeneration responses are mechanistically pivotal and therapeutically targetable, eg. in cardiomyopathies, cardiotoxicity and myocarditis.

Our researchers are investigating mechanisms that underpin developmental programming, immunomodulation, fibrosis and bioengineering in the context of both repair (conditioning the local environment, optimising wound healing) and regeneration (cell and tissue restoration). They are being applied to conditions where acute and chronic tissue injury are prominent and reach across to other diseases with an immune-fibrotic component. We are developing novel models for wider application across cardiovascular indications, and, as a new initiative, establishing cross-organ comparisons of cellular (common and distinct) mechanisms (e.g. fibrosis in heart versus liver, kidney and lung) with our collaborators. Specific new areas of focus are addressed in our three integrated sub-themes.

Sub-Theme 1: HUMAN MODEL SYSTEMS (LEAD: CHRISTOPHER TOEPFER)

This sub-theme will further develop disease-related human models which are crucial to address translational questions in R&R and to act as relevant substrates for the Drug Discovery & Delivery (DD&D) Theme.  We will optimise directed differentiation of human pluripotent stem cell-derived (hPSC)-model systems in the context of multiple interacting cardiac cell lineages, including endocardium- coronary endothelial cells, cardiomyocytes and macrophages; combining high-throughput imaging and phenomics with 3D multicellular cardioid platforms.

SUB-THEME 2: NEW CELLULAR TARGETS (LEAD: SARAH DE VAL)

This sub-theme will seek new insights into cellular and tissue responses, including repair (immune and matrix-driven) as well as regeneration (invoking adult cell reactivation, proliferation and differentiation). This will combine multi-modal omics (transcriptome/proteome/metabolome, both dispersed and spatial) and functional genomics, alongside ongoing efforts to mathematically model cell behaviour. These combined platforms will be embedded with machine learning and AI to enhance drug screening and predict outcomes following therapeutic interventions with the Big Data & Computational Science (BD&CS) Theme.

SUB-THEME 3: MECHANOBIOLOGY & TISSUE ENGINEERING (LEAD: ELLIE TZIMA)

This sub-theme will develop insights and apply discoveries from mechanobiology, bioengineering and smart materials to facilitate tissue restoration. In the developing cardiovascular system, mechanical cues, e.g. fluid shear stress, stretch, and contractility drive the formation of the heart and patterning of blood and lymphatic vessels. Such forces similarly influence disease progression and repair, e.g. driving collateral artery remodelling and revascularisation of tissues, and profoundly influence the efficacy of regenerative therapies. For example, endothelial mechanosensing orchestrates revascularisation in response to ischaemia via flow-mediated collateral remodelling. Additionally, mechanotransduction pathways essential for contractility of surviving and regenerated cardiomyocytes is compromised by fibrosis but is enhanced by biomaterials that mimic the native cardiac matrix. We will combine novel discovery and translational research approaches to understand how the mechanical microenvironment regulates cell and tissue function and repair in cardiovascular health and disease.