Activation of the ERK1/2 cascade via pulsatile interstitial fluid flow promotes cardiac tissue assembly.

Tal Dvir, Oren Levy, Michal Shachar, Yosef Granot, Smadar Cohen
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引用次数: 105

Abstract

Deciphering the cellular signals leading to cardiac muscle assembly is a major challenge in ex vivo tissue regeneration. For the first time, we demonstrate that pulsatile interstitial fluid flow in three-dimensional neonatal cardiac cell constructs can activate ERK1/2 sixfold, as compared to static-cultivated constructs. Activation of ERK1/2 was attained under physiological shear stress conditions, without activating the p38 cell death signal above its basic level. Activation of the ERK1/2 signaling cascade induced synthesis of high levels of contractile and cell-cell contact proteins by the cardiomyocytes, while its inhibition diminished the inducing effects of pulsatile flow. The pulsed medium-induced cardiac cell constructs showed improved cellularity and viability, while the regenerated cardiac tissue demonstrated some ultra-structural features of the adult myocardium. The cardiomyocytes were elongated and aligned into myofibers with defined Z-lines and multiple high-ordered sarcomeres. Numerous intercalated disks were positioned between adjacent cardiomyocytes, and deposits of collagen fibers surrounded the myofibrils. The regenerated cardiac tissue exhibited high density of connexin 43, a major protein involved in electrical cellular connections. Our research thus demonstrates that by judiciously applying fluid shear stress, cell signaling cascades can be augmented with subsequent profound effects on cardiac tissue regeneration.

通过搏动间质液流动激活ERK1/2级联可促进心脏组织组装。
破译导致心肌组装的细胞信号是体外组织再生的主要挑战。我们首次证明,在三维新生儿心脏细胞构建中,搏动间质液流动可以激活ERK1/2,是静态培养构建的六倍。在生理剪切胁迫条件下,ERK1/2被激活,而p38细胞死亡信号未被激活高于其基本水平。ERK1/2信号级联的激活诱导心肌细胞合成高水平的收缩蛋白和细胞-细胞接触蛋白,而其抑制则减弱了脉动流的诱导作用。脉冲介质诱导的心肌细胞结构表现出细胞性和活力的改善,再生的心肌组织表现出成人心肌的一些超微结构特征。心肌细胞被拉长并排列成具有明确z线的肌纤维和多个高阶肌节。邻近的心肌细胞之间有许多嵌盘,肌原纤维周围有胶原纤维沉积。再生的心脏组织显示出高密度的连接蛋白43,这是一种参与细胞电连接的主要蛋白质。因此,我们的研究表明,通过适当地施加流体剪切应力,细胞信号级联可以增强,从而对心脏组织再生产生深远的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Tissue engineering
Tissue engineering CELL & TISSUE ENGINEERING-BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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