Thymosin β-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium
Thymosin β-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium
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DOI：
10.1196/annals.1415.000
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Riley, Paul R.
中科院分区：
文献类型：
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作者：
Smart, Nicola;Risebro, Catherine A.;Riley, Paul R.
导致心肌梗塞的缺血性心脏病引起不可逆的细胞损失和瘢痕形成，并且是人类发病率和死亡率的主要原因。在心血管医学领域中，已经投入了大量的努力来寻找可以替代受损的肌细胞和/或有助于新血管形成（新血管形成）的成体心脏祖细胞，以及鉴定可以诱导这种祖细胞有助于心肌修复和侧支血管生长的关键因子。我们最近证明，肌动蛋白单体结合蛋白，胸腺素β-4（T β-4），当从心肌分泌时，为心外膜衍生细胞（EPDCs）的细胞提供旁分泌刺激，以促进其向内迁移和分化为内皮细胞和平滑肌细胞，形成冠状动脉血管系统。将T β 4在冠状血管发育中的重要作用转化到成人，我们发现用T β 4处理培养的成人外植体刺激心外膜阳性心外膜细胞的广泛生长，当它们从外植体迁移时，分化成1型前胶原、SM α A和Flk 1阳性细胞，指示成纤维细胞、平滑肌和内皮细胞;从而将成年心外膜从静止状态释放并恢复多能性。T β-4促进成人冠状血管发育并可能诱导新血管系统的能力对于心肌细胞生存至关重要，并且可能显着有助于报道的T β-4诱导的成人心脏保护和修复。T β-4目前正在进行多中心I期临床试验以治疗心血管疾病（http：www.regenerx.com），因此，深入了解T β-4诱导的修复机制是在急性心肌损伤的情况下利用肽的治疗存活、迁移和修复特性的重要步骤。
Ischemic 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 that may replace damaged muscle cells and/or contribute to new vessel formation (neovascularization) and in the identification of key factors, which may induce such progenitor cells to contribute to myocardial repair and collateral vessel growth. We recently demonstrated that the actin monomer-binding protein, thymosin beta-4 (T beta-4), when secreted from the myocardium provides a paracrine stimulus to the cells of the epicardium-derived cells (EPDCs) to promote their inward migration and differentiation into endothelial and smooth muscle cells to form the coronary vasculature. Translating this essential role for T beta-4 in coronary vessel development to the adult, we found that treatment of cultured adult explants with T beta-4 stimulated extensive outgrowth of epicardin-positive epicardial cells, which, as they migrated away from the explant, differentiated into procollagen type 1, SM alpha A, and Flk1-positive cells indicative of fibroblasts, smooth muscle, and endothelial cells; thus releasing the adult epicardium from a quiescent state and restoring pluripotency. The ability of T beta-4 to promote coronary vessel development and potentially induce new vasculature in the adult is essential for cardiomyocyte survival and could contribute significantly toward the reported T beta 4-induced cardioprotection and repair in the adult heart. T beta-4 is currently subject to multicenter phase I clinical trials for treatment of cardiovascular disease (http://www.regenerx.com), therefore, insight into the repair mechanism(s) induced by T beta-4 is an essential step toward harnessing therapeutic survival, migration, and repair properties of the peptide in the context of acute myocardial damage.