Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization

Cardiac failure has a principal underlying aetiology of ischaemic damage arising from vascular insufficiency. Molecules that regulate collateral growth in the ischaemic heart also regulate coronary vasculature formation during embryogenesis. Here we identify thymosin beta 4 (T beta 4) as essential for all aspects of coronary vessel development in mice, and demonstrate that T beta 4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. T beta 4 knockdown in the heart is accompanied by significant reduction in the pro-angiogenic cleavage product N-acetyl-seryl-aspartyl-lysyl-proline ( AcSDKP). Although injection of AcSDKP was unable to rescue T beta 4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies T beta 4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals T beta 4-induced adult epicardial cells as a viable source of vascular progenitors for continued renewal of regressed vessels at low basal level or sustained neovascularization following cardiac injury.