Investigating Thymosin beta4-mediated myocardial regeneration and anti-inflammatory wound healing in the injured heart

Coronary artery disease resulting in heart attacks is the number one killer worldwide. Approaches to curing or mitigating the effects of a heart attack have to-date principally involved surgical intervention such as coronary vessel intervention or artery bipass. In the field of biomedical research considerable effort has been invested in the search for adult or embryonic stem cells which may replace damaged cells in a diseased heart or in the identification of key factors (proteins) which may induce resident stem cells within the adult heart to initiate repair. Our studies seek to characterise one such factor, Thymosin beta4 (Tbeta4) in terms of its potential to orchestrate a DIY repair mechanism within the diseased/injured adult heart. We have significant evidence from previous studies that Tbeta4 can promote survival of heart muscle cells in an animal model of human heart attack and that it may also induce new blood vessels (a process called vasculogenesis) to help sustain the surviving healthy cells and facilitate repair of the injured heart. We will now confirm a role for Tbeta4 in initiating regeneration of lost muscle in the adult heart proper and also investigate whether this new muscle growth is accompanied by reduced inflammation and scarring to futher promote wound healing. Tbeta4 is currently in the early stages of phase I clinical trials for treatment of heart attack, the proposed studies therefore, seek to understand the mechanisms underlying how Tbeta4 may act as a regenerative therapy for heart disease.

Ischaemic heart disease leading to myocardial infarction causes irreversible cell loss and scarring and is a major cause of morbidity and mortality in humans. Significant effort in the field of cardiovascular medicine has been invested in the search for adult cardiac progenitor cells which may replace damaged muscle cells and/or contribute to new vessel formation (neovascularisation) and in the identification of key factors which may induce such progenitor cells to contribute to myocardial repair and collateral vessel growth. We recently identified the actin monomer binding protein Thymosin beta4 (Tbeta4) as essential for all stages of coronary vessel development and as an instructive cue for activating epicardial derived cells (EPDCs) of the adult mouse heart to contribute vascular progenitors for renewed vessel growth. As such Tbeta4 is a candidate for potential neovascular repair of injured myocardium. Moreover, evidence from chick-quail lineage tracing, adult zebrafish heart regeneration and mouse corneal-wounding studies collectively suggest EPDCs can give rise to de novo cardiomyocytes and that Tbeta4 has the potential to modulate inflammation post-injury. As such Tbeta4 may be a facilitator of all three key events required for complete cardiac regeneration: (i) neovascularisation, (ii) myocardial regeneration and (iii) modulation of inflammation. In the proposed studies we intend to examine the in vivo role(s) of Tbeta4 in the adult heart and investigate the potential of Tbeta4 to induce myocardial regeneration and act as an anti-inflammatory agent. We will assess both loss and gain of function mouse models and make use of an established mouse model of myocardial infarction, to examine Tbeta4 induced expansion of EPDC myocardial progenitors to form functionally integrated myocardium and inhibition of inflammatory scarring and fibrosis ro promote wound healing. In addition, we will seek to identify effectors for Tbeta4 and downstream signaling events critical for Tbeta4 cardiovascular function. Tbeta4 is currently subject to multi-centre phase 1 clinical trials for treatment of cardiovascular disease (http://www.regenerx.com), therefore, insight into the repair mechanism(s) induced by Tbeta4 is an essential step towards harnessing therapeutic survival, migration and repair properties of the peptide in the context of acute myocardial damage.