We adopt the paradigm of understanding how the heart develops during pregnancy as a first principal to inform on adult heart repair and regeneration. Our primary focus is on developmental lineages which respond during cardiovascular injury and specifically on cells derived from the outer epithelial layer of the heart, the epicardium; the endothelial cells that make up the cardiac lymphatic vasculature and tissue-resident macrophages.
E9.5 GFP+ mouse heart
1. The epicardium and epicardium-derived cells (EPDCs) line the outside of the forming heart and contribute vascular endothelial and smooth muscle cells to the coronary vasculature, interstitial fibroblasts and cardiomyocytes. The epicardium can also act as a source of signals to condition the growth of the underlying embryonic heart muscle. In the adult heart, whilst the epicardium is retained it is effectively quiescent. The application of epicardial cell biology to treatment of cardiovascular injury originates from the epicardium’s developmental plasticity and from the ability to reactivate these properties in the adult heart. The embryology underlying EPDCs sets them apart from other adult cardiac stem cell populations and provides the rational underpinning prospective pharmacological and genetic manipulations aimed at mobilizing and guiding these cells towards regenerating the injured adult heart.
Adult mouse heart section: muscle (red); epicardium/vessels (green)
Epicardium and coronary vessels (red); heart muscle (blue)
• To define the regenerative potential of activated adult EPDCs, as directly compared to their developmental counterparts
• To determine the molecular signature which defines the active population and mechanistically how these cells can be reprogrammed towards embryonic potency
• To identify EPDC-derived signals which may induce myocardial and vascular repair
• To identify novel inducers and signaling pathways which might be extrapolated to human EPDCs and facilitate drug discovery.
2. The cardiac lymphatic vessels have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple cre-lox based lineage tracing and genetic targeting of Prox1 has revealed a potential contribution from the hemogenic endothelium during development. This suggests lineage heterogeneity which may impact on the developing lymphatics and their response to injury. In the adult heart, myocardial infarction (MI) promotes a significant lymphangiogenic response, which can augmented by treatment with VEGF-C resulting in improved cardiac function.
Wholemount mouse heart at E16.5; coronary veins (green); lymphatics (red)
Adult mouse heart 7-days post-MI: expanded lymphatic network (boxed) in blue (asterix indicates site of injury)
• To understand the mechanisms underpinning developmental lymphangiogenesis in response to adult heart injury and identify the source of inducing signals
• To determine the effects of increased lymphatic vessel density on tissue fluid clearance, oedema and inflammation.
• To identify novel small molecule inducers of human lymphangiogenesis
3. Tissue-resident macrophages, derived from sources of embryonic progenitors (including those of the yolk sac), populate the developing heart and have been implicated in remodelling the developing coronary plexus. Whether embryonic-derived macrophages play other roles in heart development remains unknown as does their precise contribution to the immune response and tissue repair during adult cardiovascular injury.
The developing cardiac lymphatic vessels and tissue-resident macrophages
• To investigate a role for embryonic macrophages in cardiovascular development
• To determine the role of tissue-resident macrophages in response to cardiovascular injury
• To extrapolate to the total macrophage population and identify discrete molecular signatures and function during regeneration versus fibrosis/scarring
• To target immune cell-derived signals for conditioning the local inflammatory and fibrotic environment for cell integration and tissue restoration