Thymosin |[bgr]|4 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 |[bgr]|4 (T|[bgr]|4) as essential for all aspects of coronary vessel development in mice, and demonstrate that T|[bgr]|4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. T|[bgr]|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|[bgr]|4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies T|[bgr]|4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals T|[bgr]|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.

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