MYOFIBROBLASTS AND THE INFARCTED HEART

心力衰竭是一种主要的健康问题，最常见于既往有心肌梗死（MI）的患者。 纤维化被认为是缺血性心肌病中不良结构重塑的主要组成部分。 肌成纤维细胞（myofibroblasts，myoFbs）是一种表型转化的成纤维细胞样细胞，负责心肌梗死后的纤维形成和细胞外基质重塑。 MyoFbs具有介于成纤维细胞之间的特征（例如，胶原合成）和平滑肌细胞（例如，α-平滑肌肌动蛋白，ASMA），它们创造了一个动态的微环境。 MI后修复涉及基质降解、细胞生长和生长空间控制的初始组合，随后是胶原蛋白合成和沉积。 我们的第一个目的是鉴定和表征心肌梗死后的myoFb祖细胞和信号，通过i）通过用β-半乳糖苷酶基因离体标记分离的Fcs，静脉内注射标记的Fcs并监测它们在梗死部位的出现来确定循环纤维细胞（Fcs）或间质成纤维细胞（IFbs）是否是myoFb的祖细胞，和ii）研究信号传导分子如NF-κ B的作用，TGF-β 1和激活MMP-1的酪氨酸激酶。 在我们的第二个目标中，我们将确定组织极性基因frizzled 2（fz 2）对myoFb排列的空间控制和myoFb衍生的纤维组织形成中涉及的因素的作用，通过i）研究fz 2和wnt基因在梗死心脏中的表达，ii）解决fz 2在梗死扩展和室壁瘤中的表达，iii）鉴定调节myoFb基质沉积的因素。 我们的第三个目的是通过i）研究负责特定myoFb表型的连续产生与持续的信号及其胶原蛋白周转，ii）确定促凋亡基因如Bax和凋亡抑制剂如Bc 12对myoFb持续的作用，和iii）确定心室卸载的作用，来确定myoFb持续及其纤维化活性的机制（应力松弛）对myoFb命运、表型和活性的影响。 最后，我们将这些观察结果外推到患有缺血性心肌病的人类心脏。深入了解这些组织修复的基本问题将有助于保护性干预措施的前景，这将使缺血性心力衰竭的有效管理。

Heart failure, a major health problem, appears most commonly in patients with previous myocardial infarction (MI). Fibrosis is considered a major component of adverse structural remodeling found in ischemic cardiomyopathy. Myofibroblasts (myoFbs), phenotypically transformed fibroblast-like cells, are responsible for fibrogenesis and extracellular matrix remodeling following MI. MyoFbs have characteristics intermediate between fibroblasts (e.g., collagen synthesis) and smooth muscle cells (e.g., alpha-smooth muscle actin, ASMA) and they create a dynamic microenvironment. Repair postMI involves an initial combination of matrix degradation, cell growth and spatial control of growth followed by collagen synthesis and deposition. Our first aim is to identify and characterize myoFb progenitors and signals following MI by i) determining whether circulating fibrocytes (Fcs) or interstitial fibroblasts (IFbs) are progenitors of myoFb by tagging isolated Fcs ex vivo with beta-galactosidase gene, intravenous injection of tagged Fcs and monitoring their appearance at the infarct site, and ii) studying the role of signalling molecules such as NF-kappaB, TGF-beta1 and tyrosine kinases that activate MMP-1. In our second aim, we will determine the role of tissue polarity gene frizzled 2 (fz2) on spatial control of myoFb alignment and factors involved in myoFb-derived fibrous tissue formation by i) studying fz2 and wnt gene expression in the infarcted heart, ii) addressing fz2 expression in infarct expansion and ventricular aneurysm, and iii) identifying factors regulating myoFb matrix deposition. Our third aim is to determine mechanisms of myoFb persistence and their fibrogenic activity by i) studying signals responsible for continuous generation vs persistence of a particular myoFb phenotype and their collagen turnover, ii) determining the role of proapoptotic genes such as Bax and inhibitors of apoptosis, such as Bc12 on myoFb persistence, and iii) determining the role of ventricular unloading (stress relaxation) on myoFb fate, phenotype and activity. Finally, we extrapolate these observations to human hearts with ischemic cardiomyopathy. Insights into these fundamental questions of tissue repair will contribute to prospects for protective interventions that will enable effective management of heart failure of ischemic origin.