En route to mending a broken heart
Professor Paul Riley
Friday, 06 February 2015, 1pm to 1.30pm
Sherrington Large Lecture Theatre, Sherrington Building, off South Parks Road OX1 3PT
If you have a question about this talk, please contact Sarah Noujaim.
Cardiovascular disease is the number one killer worldwide, of which the major contributor is blocked coronary arteries (atherosclerosis) leading to a heart attack (myocardial infarction). The adult mammalian/human heart has a limited capacity to repair itself following an “attack” and instead undergoes scarring and pathological remodeling which ultimately leads to heart failure. Thus, the only current cure is heart transplantation which is confounded by a dearth of available hearts and immune rejection of the donor organ. In recent years alternate cell-based methods of heart repair have emerged with therapeutic potential and have been fast-tracked to clinical trials involving the transplantation of various cell types into patient hearts in an effort to regrow new muscle and blood vessels. Unfortunately, results to-date have been disappointingly modest, with little or no evidence of new cell growth and only marginal, short-term improvement in heart function.
As an alternative, we adopt the paradigm of understanding how the heart develops during pregnancy as a first principal to inform on adult heart repair and regeneration. We focus on the epicardium and epicardium-derived cells (EPDCs) which line the outside of the forming heart and contribute vascular endothelial and smooth muscle cells (to make up the heart blood vessels), interstitial fibroblasts (the so-called “skeleton” of the heart) and cardiomyocytes (heart muscle cells). 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 thought to be effectively dormant. We have sought to extrapolate the developmental potential of the epicardium to the adult heart by stimulating dormant epicardial cells using a protein called Thymosin 4 (T4). We reveal the adult cells can reactivate embryonic epicardial genes in response to T4 and heart injury, a hallmark of heart regeneration in the adult zebrafish and mouse pup during the first week of life (neonatal mouse); subsequently activated EPD Cs give rise to new muscle and blood vessel cells at the site of injury.
Whilst a significant step towards restoring lost heart tissue, the direct contribution from the epicardium is inadequate for full repair. Therefore, we are adopting two parallel approaches to improve the process: i) screening human patient epicardial cells to finds molecules (“drugs”) which might enhance activation and more efficiently generate new functional heart cells and ii) studying adult zebrafish and neonatal mice to identify evolutionary-conserved epicardial signals, which might both function during development and further drive regeneration of the adult mammalian/human heart.
This work was generously supported by the British Heart Foundation: DPAG