Svystonyuk Daniyil A, Ngu Janet M C, Mewhort Holly E M, Lipon Brodie D, Teng Guoqi, Guzzardi David G, Malik Getanshu, Belke Darrell D, Fedak Paul W M
Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada.
J Transl Med. 2015 May 7;13:147. doi: 10.1186/s12967-015-0510-4.
Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.
We examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.
Human cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.
TGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.
LMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.
组织纤维化和心室重构是衰竭心脏的标志，也是各种病因导致心力衰竭的最终共同途径。促纤维化细胞因子转化生长因子-β1（TGFβ1）的持续升高会诱导心肌成纤维细胞介导的纤维化和进行性结构组织重构。
我们研究了低分子量成纤维细胞生长因子（LMW-FGF-2）对人心脏成纤维细胞介导的细胞外基质（ECM）失调和重构的影响。
在心脏直视手术期间获取人心脏活检组织，分离、传代心肌成纤维细胞，并接种于I型胶原基质中。为诱导心肌成纤维细胞活化和ECM重构，将接种了心肌成纤维细胞的胶原凝胶暴露于TGFβ1。在有LMW-FGF-2存在和不存在的情况下，测定ECM收缩、心肌成纤维细胞活化、ECM失调和细胞凋亡的程度，并进行比较。使用新型漂浮尼龙网格支撑的薄胶原凝胶培养平台系统，利用共聚焦显微镜对分离的单个细胞周围的心肌成纤维细胞活化和局部ECM重构进行成像，并通过图像分析进行定量。
TGFβ1诱导了显著的心肌成纤维细胞活化和ECM失调，表现为胶原凝胶收缩、结构性ECM重构、胶原合成、ECM降解以及TIMP表达改变。LMW-FGF-2显著减弱了TGFβ1诱导的心肌成纤维细胞介导的ECM重构。使用心室或心房来源的心肌成纤维细胞时，这些观察结果相似。此外，首次在单个细胞中观察到，LMW-FGF-2可减弱心肌成纤维细胞活化并防止局部细胞介导的ECM扰动。
LMW-FGF-2可减弱人心脏成纤维细胞介导的ECM重构，并可能预防各种结构性心脏病患者进行性的适应性不良心室重构和组织纤维化。
