MYOFIBROBLASTS AND THE INFARCTED HEART

心力衰竭是一个主要的健康问题，最常出现在既往有心肌梗死(MI)的患者中。纤维化被认为是缺血性心肌病中发现的不良结构重构的主要组成部分。肌成纤维细胞(MyoFbs)是一种表型转化的成纤维细胞样细胞，在心肌梗死后的纤维化形成和细胞外基质重构中起重要作用。MyoFbs具有介于成纤维细胞(如胶原合成)和平滑肌细胞(如α-平滑肌肌动蛋白，ASMA)之间的特征，它们创造了一个动态的微环境。心肌梗死后的修复包括基质降解、细胞生长和生长的空间控制的初始组合，随后是胶原合成和沉积。我们的第一个目标是鉴定和表征心肌梗死后的myoFb前体细胞和信号，方法如下：i)通过用β-半乳糖苷酶基因标记体外分离的循环纤维细胞(FCs)和间质成纤维细胞(IFbs)，静脉注射标记的FCs并监测它们在梗死部位的表现，来确定循环纤维细胞(FCs)或间质成纤维细胞(IFbs)是myoFb的前体细胞；ii)研究信号分子如核因子-kappaB、转化生长因子-β1和酪氨酸激酶激活基质金属蛋白酶-1(MMP1)的作用。在我们的第二个目标中，我们将通过i)研究fz2和WNT基因在梗死心脏中的表达，ii)解决fz2在梗塞扩大和室壁瘤中的表达，以及iii)确定调控myoFb基质沉积的因素，来确定组织极性基因fz2在myoFb排列的空间调控中的作用和参与myoFb衍生纤维组织形成的因素。我们的第三个目标是通过以下方面来确定myoFb持续性及其纤维化活性的机制：i)研究负责特定myoFb表型持续产生和持续性的信号及其胶原周转；ii)确定促凋亡基因(如bax)和凋亡抑制物(如bc12)在myoFb持续性中的作用；以及iii)确定心室卸载(应力松弛)对myoFb命运、表型和活性的作用。最后，我们将这些观察结果外推到患有缺血性心肌病的人的心脏。对组织修复的这些基本问题的深入了解将有助于保护性干预的前景，从而使缺血性心力衰竭能够得到有效的管理。

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.