Engineering vascularized cardiac muscle.

描述（由申请人提供）：由于心脏病夺去的生命比所有癌症加起来还要多，对开发新的有效的心脏再生治疗方式的需求正在扩大。心脏组织工程具有增强组织修复的能力，为心脏再生研究提供了真实的组织模型。困难在于我们在多尺度上忠实地再生天然心肌各向异性结构和功能特性的能力有限。我们提出了一种全新的策略来实现这一目标，即形成一个可灌注血液的分支血管网络，并将该网络作为构建心脏组织的模板。我们的假设是，地形线索（由天然心脏基质氢制成的“凹槽和山脊”支架提供）、分子调节因子（结合在水凝胶中并由支持细胞分泌）和来自人类诱导多能干细胞（iPSC）的心肌细胞的体外调节（机电式和缺氧）的协同应用将重现类似天然心脏的生态位，并导致功能性组织的形成。我们建议在体外和体内心脏再生的定量研究中严格检验这一假设。我们的主要兴趣是改善工程心脏组织的成熟、存活和功能的因素和机制。将实现三个具体目标。目的1是通过在动脉/静脉系统中定向毛细血管生长来建立分支的人体血管网络。目的二是在血管网络周围设计人类心肌，使其功能成熟，并提高其在缺氧条件下的存活率。目的3：在心脏缺血动物模型中评价血管化心脏移植物的功能。在这三个目标中，重点是通过调节成熟、生存和人类细胞进入血管化心肌的功能组装来控制心脏再生的生物物理。我们相信这项工作对定量生物学研究和开发治疗心脏病的实用组织工程模式具有重要意义。

DESCRIPTION (provided by applicant): The need for developing new and effective treatment modalities for cardiac regeneration is expanding, as cardiac disease continues to take more human lives than all cancer combined. Cardiac tissue engineering has great capacity to enhance tissue repair and to provide realistic tissue models for studying cardiac regeneration. The difficulties arise from our limited ability to faithfully regenerate at multiple scales the anisotropic structural and functional properties of native heart muscle. We propose a radically novel strategy to reach this goal, by forming a branching vascular network perfusable with blood and using this network as a template to build cardiac tissue. Our hypothesis is that the synergistic application of topographical cues (provided by a "groove and ridge" scaffold made of native heart matrix hydrogen), molecular regulatory factors (incorporated in hydrogel and secreted by supporting cells) and in vitro conditioning (electromechanical and hypoxic) of cardiomyocytes derived from human induced pluripotent stem cell (iPSC) will recapitulate a native-like cardiac niche and lead to the formation of functional tissue. We propose to rigorously test this hypothesis in quantitative studies of cardiac regeneration, in vitro and in vivo. Our mai interest is in the factors and mechanisms that improve the maturity, survival and function of engineered cardiac tissue. Three specific aims will be pursued. Aim 1 is to establish a branching human vascular network by directed capillary outgrowth within an artery/vein system. Aim 2 is to engineer human cardiac muscle around the vascular network, mature its function, and enhance its survival under hypoxic conditions. Aim 3 is to functionally evaluate vascularized cardiac grafts in an animal model of cardiac ischemia. In all three aims, the focus is on biophysical control of cardiac regeneration by modulation of maturation, survival and functional assembly of human cells into vascularized cardiac muscle. We believe that this work has significance for quantitative biological research and the development of practical tissue-engineering modalities for treating heart disease.