Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip
Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip
复制标题
DOI：
10.1073/pnas.1304913110
复制
发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Parker, Kevin Kit
中科院分区：
文献类型：
--
作者：
McCain, Megan L.;Sheehy, Sean P.;Parker, Kevin Kit
缺乏用于治疗心脏病的强大的医学治疗剂管道可能部分归因于缺乏概括健康和患病心肌的基本结构-功能关系的体外模型。我们设计并构建了一个系统，通过在可拉伸芯片上对工程化层状心室组织施加周期性拉伸来模拟体外机械过载。为了测试我们的模型，我们量化了基因表达、肌细胞结构、钙处理和收缩功能的变化，并将我们的结果与几十年的动物研究和临床观察进行了比较。周期性牵张激活的基因表达谱特征的病理性重塑，包括降低α-β-肌球蛋白重链的比例，并诱导适应不良的变化，肌细胞的形状和肌节排列。在拉伸的组织中，钙瞬变类似于在衰竭的肌细胞中报道的那些，并且峰值收缩应力显著降低。我们的研究结果表明，失败的心肌，定义的遗传，结构和功能，可以复制在体外微系统忠实地重演的结构和机械微环境的患病心脏。
The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structure-function relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased alpha- to beta-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart.