Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization

Abstract

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 beta4 (Tbeta4) as essential for all aspects of coronary vessel development in mice, and demonstrate that Tbeta4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. Tbeta4 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 Tbeta4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies Tbeta4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals Tbeta4-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.

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

“…The epicardium has been reported to play an active role during normal cardiomyogenesis 25, while it becomes quiescent after birth 26. Although the mammalian epicardium is activated after MI, the number of the activated cells is insufficient for myocardium repair 27, 28.…”

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…Thus, MRTF-A is located at the crossroads of myocyte and vessel regeneration in hibernating myocardium. T 4, the most abundant G-actin-binding peptide of the cytosol, is capable of inducing vessel growth via endothelial migration and sprouting 21,36 . An essential role of MRTF-A in T 4 angiogenic signalling was established in vitro and in vivo, since MRFT-AshRNA was capable of abrogating endothelial migration and sprouting (Fig.…”

MicroRNA-processing Enzyme Dicer Is Required in Epicardium for Coronary Vasculature Development

“…In addition to its role in cardiac development, the epicardium also regulates cardiac regeneration after injury in lower vertebrates (9,10). In mammals, the regeneration potential of cardiac tissue is limited, but epicardium is activated and supports formation of new blood vessels by triggering differentiation of EPDCs into fibroblast, smooth muscles, and endothelial cells after myocardial infarction (11).…”