Development, maintenance and regeneration of the cardiovascular system
The principle of redeploying embryonic mechanisms in the adult heart for cardiac repair
Ischaemic heart disease resulting in 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. 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. The ability to revive ordinarily dormant EPDCs lies in the identification of key molecular cues used in embryonic heart development. Thymosin β4 (Tβ4) restores the quiescent adult epicardium to its multipotent embryonic state and treatment of injured mouse hearts induces dramatic EPDC reactivation, formation of a new vessel network to enhance blood flow to oxygen-starved muscle, as well as production of de novo functional cardiomyocytes to improve recovery of the heart after MI.
Restoring blood flow to the ischaemic heart
Ongoing research seeks to augment the efficiency of EPDC-mediated regeneration based on:
i) understanding mechanisms by which Tβ4 induces epicardial activation and influences EPDC fate.
ii) investigating non-coding RNA regulatory networks that may mediate epicardial (re)activation.
EPDCs: potential to regenerate the inured heart
A role for Thymosin β4 in maintenance of healthy vasculature
Damage to the endothelial cells that line blood vessels causes accumulation of cholesterol, immune cell infiltration and destruction of muscle and elastic layers, to weaken the vessel. Rupture of weakened vessels causes life-threatening events (heart attack, stroke or aneurysm). We defined an essential requirement for endothelial-secreted Tβ4 in mural cell differentiation for the development of stable vessels in the embryo. We are currently investigating the possibility that Tβ4 functions to maintain vascular stability throughout life and whether it may be protective in the context of vascular injury.