Engineering vascularized cardiac muscle.

描述(由申请人提供)：随着心脏疾病夺走的生命继续超过所有癌症的总和，开发新的和有效的心脏再生治疗方式的需求正在扩大。心脏组织工程具有促进组织修复和为心脏再生研究提供现实的组织模型的巨大能力。困难来自于我们在多个尺度上忠实地再生天然心肌的各向异性结构和功能特性的有限能力。我们提出了一种全新的策略来实现这一目标，通过形成一个可与血液灌流的分支血管网络，并以此网络为模板来构建心脏组织。我们的假设是，由人诱导的多能干细胞(IPSC)来源的心肌细胞在地形提示(由天然心脏基质氢制成的“凹槽和脊状”支架提供)、分子调控因子(掺入水凝胶并由支持细胞分泌)和体外调节(机电和低氧)的协同应用下，将概括出类似天然的心脏生态位，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说。我们最感兴趣的是改善工程心脏组织成熟度、存活率和功能的因素和机制。将追求三个具体目标。目标1是通过在动/静脉系统内定向的毛细血管生长来建立一个分支的人类血管网络。目的2是在血管网络周围设计人类心肌，成熟其功能，提高其在低氧条件下的存活率。目的3是在心肌缺血的动物模型中评价带血管的心脏移植物的功能。在这三个目标中，重点都是通过调节人类细胞的成熟、存活和功能组装成血管化的心肌来控制心脏再生。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.