Enhancing survival and function of engineered cardiac tissue

描述(由申请人提供)： 在从人类干细胞获得功能性心肌细胞以及开发利用这些细胞的组织工程策略方面已经取得了显著的进展。然而，心脏移植物的存活和功能仍然很差，至少有两个原因：组织工程策略没有提供必要的细胞保护和调节，以及受伤心脏的缺血/炎症环境被完全忽视。我们推测，通过在植入时控制移植物中的细胞偶联以及移植物与宿主环境的相互作用，可以克服开发有效的心肌梗死细胞疗法的一些现有障碍。为了解决这种高度跨学科的问题，我们成立了一个由两个实验室组成的协会，这些实验室在心脏组织工程(哥伦比亚大学)和炎症反应分析(阿尔伯特·爱因斯坦医学院)方面提供强大的专业知识。在过去的六个月里，我们进行了广泛的初步研究，以形成工作假设，发展调查方法，并论证关键实验方法的可行性。心脏组织移植物将在电刺激和炎症细胞因子存在的情况下，从人诱导性多能干细胞来源的心肌细胞中生长出来。我们设计了一个具有炎症环境、电刺激应用和功能成像能力的3D人体组织平台，采用方便的96孔格式。该平台将使用心肌梗死的动物植入模型进行验证。我们的工作假设是，心脏细胞、炎症细胞和细胞因子之间的多维相互作用可以在治疗上倾斜，以最大限度地提高移植物的存活率和功能。在目标1中，我们将表征心脏移植物对炎性细胞因子和低氧的反应，并评估细胞保护性细胞因子对移植物预适应的影响。在目标2中，我们将评估工程化心脏移植物在急性心肌缺血动物模型中的作用。我们的长期目标是确定心脏保护措施，从而在心脏移植物植入梗死床后改善其存活率和功能。(摘要结束)

DESCRIPTION (provided by applicant): Remarkable progress has been made in deriving functional cardiomyocytes from human stem cells, and developing tissue-engineering strategies for utilization of these cells. However, the survival and function of cardiac grafts remain poor, for at least two reasons: tissue-engineering strategies do not provide the necessary cell protection and conditioning, and the ischemic/inflammatory environment of the injured heart is completely overlooked. We postulate that some of the existing barriers to the development of effective cell therapies for myocardial infarction can be overcome by manipulating cell coupling in the graft at the time of implantation and graft interactions with the host environment. To tackle such a highly interdisciplinary problem, we formed an association of two laboratories providing strong expertise in cardiac tissue engineering (Columbia University) and analysis of inflammatory responses (Albert Einstein College of Medicine). Over the last six months, we conducted extensive preliminary studies to formulate a working hypothesis, develop the investigational approach, and demonstrate feasibility of key experimental methods. Cardiac tissue grafts will be grown from human iPS-derived cardiomyocytes, with electrical stimulation, and in the presence of inflammatory cytokines. We designed a 3D human tissue platform with critical components of the inflammatory environment, application of electrical stimulation and capability for functional imaging, in a convenient 96-well format. This platform will be validated using an animal implantation model of cardiac infarction. Our working hypothesis is that the multidimensional interplay between cardiac cells, inflammatory cells and cytokines can be therapeutically skewed to maximize graft survival and function. In Aim 1, we will characterize the responses of cardiac grafts to inflammatory cytokines and hypoxia, and evaluate the effects of graft conditioning by cell-protective cytokines. In Aim 2, we will evaluate engineered cardiac grafts in an animal model of acute cardiac ischemia. Our long-term goal is to identify cardio-protective measures leading to improved survival and function of cardiac grafts following their implantation into the infarct bed. (End of Abstract)