Research Aims & Objectives
Development and regeneration of the heart and coronary vasculature
Our ongoing research seeks to enhance the inadequate regenerative capacity of the adult mammalian heart based on:
- understanding embryonic mechanisms which influence epicardial function
- investigating mechanisms of embryonic coronary vessel formation
- developing strategies to redeploy embryonic mechanisms for neovascularisation and regeneration of the ischaemic adult heart
Details of research interests
The principle of redeploying embryonic mechanisms in the adult heart for cardiac repair Myocardial infarction (MI) causes irreversible cell loss and scarring, leading to adverse remodelling and heart failure. Given the heart’s inadequate capacity for self-repair, significant effort has been invested in regenerative strategies to replace damaged muscle cells and revascularise the heart. Studies of the embryonic heart, including the identification of cardiovascular progenitors, have informed strategies to manipulate a regenerative response in the adult and this paradigm is the underlying basis of our research. Specifically, we revealed the potential to reactivate quiescent adult epicardial cells to unleash a source of cardiac progenitors for ‘DIY’ repair of the injured heart (Smart et al., Nature 2007 & 2011). Similarly, from our studies on vascular development (Smart et al., Nat. Commun. 2010; Rossdeutsch et al., Circ. Res. 2012), novel insights have emerged into mechanisms that are important for maintenance of vessel stability throughout adult life (Munshaw et al., J. Clin. Invest. 2021) and neovascularisation of the ischaemic heart (Dubé et al., JCI Insight. 2017).
Due to their fundamental role in heart development, epicardium-derived cells (EPDCs) have emerged as a population with potential to regenerate myocardium and coronary vasculature (Redpath and Smart, Stem Cells Transl Med, 2020). The ability to revive quiescent EPDCs lies in the identification of key molecular cues used in embryonic heart development (Smart et al., Nature 2007). Mobilisation of epicardial cells into the adult myocardium is dependent upon epithelial to mesenchymal transformation (EMT), a critical event in the embryonic heart that is poorly recapitulated in the adult. Profiling the epicardium and its derivatives at the single cell level (Lupu et al., Stem Cell Reports, 2020) has revealed important insights into the underlying mechanisms and ongoing projects investigate the signalling and regulatory pathways that control EMT.
During development, the endothelium of the coronary vasculature derives from the sinus venosus and endocardium. In response to injury, these lineages are partly reactivated, as an endogenous attempt to revascularise the ischaemic heart (Dubé et al., JCI Insight, 2017), however, there are fundamental differences between the regulatory pathways controlling vessel growth in the embryo and adult and between regenerative (zebrafish and neonatal mouse) and non-regenerative (adult mouse) models (Payne et al., Nat. Commun, 2019). Comparative analyses allow us to identify key mechanisms that may be extrapolated and targeted in the adult mammalian heart to enhance repair.
- Dr Jacinta Kalisch-Smith
- Dr Ian McCracken
- Dr Andia Redpath
- Dr Andrew Robson (visiting)
Collaborators - Oxford:
Collaborators - External:
- Enrique Lara-Pezzi, CNIC, Madrid
- Amer Rana, Cambridge/ UEA
- Linda Troeberg, UEA
- Bin Zhou, Shanghai
- British Heart Foundation
- Medical Research Council
While sharing research findings with the scientific community is immensely rewarding, we derive great satisfaction from presenting our research to the public. Our team’s outreach activities have included invited lectures at schools and Science Cafés, public debates, laboratory visits for local school pupils and interactive presentations at the Oxford Science + Ideas Festival. As a BHF research fellow, Nicola regularly hosts lab tours for BHF supporters, has presented a seminar for the administrative staff at BHF headquarters and featured in various videos, newspaper articles and the charity’s “Fight for Every Heartbeat” national television advertising campaign. Nicola recently recorded a podcast for Oxford Sparks “How do you mend a broken heart?” and presented a Lady Dervorguilla seminar, hosted by Balliol College, to feature leading female academics in Oxford.