Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
J Cell Mol Med. 2012 Oct;16(10):2429-39. doi: 10.1111/j.1582-4934.2012.01560.x.
After a myocardial infarction, thinning and expansion of the fibrotic scar contribute to progressive heart failure. The loss of elastin is a major contributor to adverse extracellular matrix remodelling of the infarcted heart, and restoration of the elastic properties of the infarct region can prevent ventricular dysfunction. We implanted cells genetically modified to overexpress elastin to re-establish the elastic properties of the infarcted myocardium and prevent cardiac failure. A full-length human elastin cDNA was cloned, subcloned into an adenoviral vector and then transduced into rat bone marrow stromal cells (BMSCs). In vitro studies showed that BMSCs expressed the elastin protein, which was deposited into the extracellular matrix. Transduced BMSCs were injected into the infarcted myocardium of adult rats. Control groups received either BMSCs transduced with the green fluorescent protein gene or medium alone. Elastin deposition in the infarcted myocardium was associated with preservation of myocardial tissue structural integrity (by birefringence of polarized light; P < 0.05 versus controls). As a result, infarct scar thickness and diastolic compliance were maintained and infarct expansion was prevented (P < 0.05 versus controls). Over a 9-week period, rats implanted with BMSCs demonstrated better cardiac function than medium controls; however, rats receiving BMSCs overexpressing elastin showed the greatest functional improvement (P < 0.01). Overexpression of elastin in the infarcted heart preserved the elastic structure of the extracellular matrix, which, in turn, preserved diastolic function, prevented ventricular dilation and preserved cardiac function. This cell-based gene therapy provides a new approach to cardiac regeneration.
心肌梗死后，纤维化瘢痕的变薄和扩张导致进行性心力衰竭。弹性蛋白的丧失是梗死心脏细胞外基质进行性重塑的主要原因，恢复梗死区域的弹性特性可以预防心室功能障碍。我们植入了经过基因修饰以过表达弹性蛋白的细胞，以重建梗死心肌的弹性特性并预防心力衰竭。克隆了全长人弹性蛋白 cDNA，亚克隆到腺病毒载体中，然后转导到大鼠骨髓基质细胞（BMSCs）中。体外研究表明，BMSCs 表达弹性蛋白，该蛋白被沉积到细胞外基质中。转导的 BMSCs 被注射到成年大鼠的梗死心肌中。对照组接受转导绿色荧光蛋白基因的 BMSCs 或培养基。在梗死心肌中沉积弹性蛋白与保持心肌组织结构完整性有关（偏振光双折射；P<0.05 与对照组相比）。结果，梗死瘢痕厚度和舒张顺应性得以维持，梗死扩张得以预防（P<0.05 与对照组相比）。在 9 周的时间内，植入 BMSCs 的大鼠表现出比培养基对照组更好的心脏功能；然而，接受过表达弹性蛋白的 BMSCs 治疗的大鼠表现出最大的功能改善（P<0.01）。在梗死心脏中过表达弹性蛋白可以保持细胞外基质的弹性结构，这反过来又可以保持舒张功能，防止心室扩张并保持心脏功能。这种基于细胞的基因治疗为心脏再生提供了一种新方法。
