Engineering vascularized cardiac muscle.

描述（由申请人提供）：开发新的有效的心脏再生治疗方式的需求正在扩大，因为心脏病继续夺去比所有癌症加起来更多的人的生命。心脏组织工程在促进组织修复和为研究心脏再生提供真实的组织模型方面具有巨大的潜力。困难来自于我们有限的能力，忠实地再生在多个尺度的天然心肌的各向异性的结构和功能特性。我们提出了一种全新的策略来实现这一目标，通过形成一个分支血管网络灌注血液，并使用该网络作为模板来建立心脏组织。我们的假设是地形线索的协同应用（由天然心脏基质氢制成的“槽脊”支架提供），分子调节因子（掺入水凝胶中并由支持细胞分泌）和体外调节（机电和缺氧）的心肌细胞衍生自人类诱导多能干细胞（iPSC）将重演一个天然的-就像心脏龛一样，并导致功能组织的形成。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。我们的主要兴趣是提高工程化心脏组织的成熟度、存活率和功能的因素和机制。将追求三个具体目标。目的1是通过在动脉/静脉系统内定向毛细血管生长来建立分支的人体血管网络。目标2是在血管网络周围构建人类心肌，使其功能成熟，并提高其在缺氧条件下的存活率。目的3是在心肌缺血动物模型中评价血管化心脏移植物的功能。在所有三个目标中，重点是通过调节人细胞成熟、存活和功能组装成血管化心肌来生物物理控制心脏再生。我们相信，这项工作具有重要意义的定量生物学研究和实用的组织工程治疗心脏病的方式的发展。

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.