Biomimetic cardiac patch capable of rapid angiogenesis

摘要 心力衰竭在全球范围内的流行比例正在上升，影响着全球2300多万人 其中仅在美国就有580万人。急性心肌梗死(MI)导致缺血性 心肌病是射血分数降低的心力衰竭最常见的病因。心肌细胞 来源于人类可诱导多能干细胞(hiPSC-CMS)是一种很有前途的新型自体细胞- 心脏病的基础治疗。干细胞心脏再生目前面临的障碍 治疗包括细胞存活和成熟，延长的心肌细胞的各向异性结构和排列， 心脏补片与天然心肌的机电结合，以及快速血管生成 支持再生心肌中的心肌细胞。这项提议的主要目标是开发一种 厚的、成熟的、有功能的心脏组织，不仅具有天然组织的各向异性，而且还 刺激快速血管生成(1周)。我们假设一个功能多层的组合 HIPSC-CMS心脏补片与bFGF支架配对显著改善早期和晚期心肌细胞 存活并促进快速血管生成。这一假设将在以下三个具体目标中得到检验； 目的1)这一目标将决定HiPSC-CMS的成熟度、收缩功能和细胞存活率。 层状排列的纳米纤维心脏贴片的体外实验，目的2)这一目的将建立释放bFGF的有效性 支架在模拟缺血条件下提高HiPSC-CMS存活率和促进快速血管生成 体外，目的3)这一目的将确定移植的多层HiPSC-CMS心脏补片配对的效果 碱性成纤维细胞生长因子支架对心肌梗死后心功能、细胞植入、血管生成、组织的影响 体内心肌梗死大鼠模型中的氧合作用和机电一体化。总体而言，这项提议将 建立一种创新的基于心肌细胞的治疗策略，其基础是：(I)结合人类 IPSC来源的末端分化的心肌细胞与可生物降解的定向纳米纤维支架，(Ii)bFGF- 释放支架以促进早期细胞存活和快速血管生成，以及(Iii)无创监测 体内心肌组织氧合和细胞植入。这个项目的结果将使我们能够 开发一种新的心脏补片，用于移植成用于修复受损心肌梗死的大型动物临床模型 心。

ABSTRACT Heart failure is on the rise in epidemic global proportions affecting more than 23 million people worldwide including 5.8 million individuals in the US alone. Acute myocardial infarction (MI) leading to ischemic cardiomyopathy is the most common etiology for decreased ejection fraction heart failure. Cardiomyocytes derived from the human inducible pluripotent stem cells (hiPSC-CMs) are promising as a novel autologous cell- based therapy in heart disease. The current obstacles for cardiac regeneration using stem-cell based therapies include cell survival and maturity, anisotropic structure and alignment of elongated cardiomyocytes, electro-mechanical integration of the cardiac patch with the native myocardium, and rapid angiogenesis to support cardiomyocytes in the regenerating myocardium. The main objective of this proposal is to develop a thick mature and functional cardiac tissue that not only has the anisotropy of the native tissue but also stimulates rapid angiogenesis (1-week). We hypothesize that a combination of a functional multi-layered hiPSC-CMs cardiac patch paired with a bFGF scaffold significantly improves the early and late cardiomyocyte survival and promotes rapid angiogenesis. This hypothesis will be tested in the following three specific aims; Aim 1) This aim will determine the maturity, contractile function, and cell survivability of a hiPSC-CMs multi- layered aligned nanofiber cardiac patch in vitro, Aim 2) This aim will establish the efficacy of bFGF releasing scaffolds to enhance hiPSC-CMs survival and promote rapid angiogenesis in simulated ischemic conditions in vitro, Aim 3) This aim will determine efficacy of the transplanted multi-layered hiPSC-CMs cardiac patch paired with bFGF scaffold following myocardial infarction on cardiac function, cell engraftment, angiogenesis, tissue oxygenation and electro-mechanical integration, in an in vivo rat model of MI. Overall, this proposal will establish an innovative myocardial cell-based therapeutic strategy based on, (i) the combination of human iPSC-derived terminal differentiated cardiomyocytes with a biodegradable aligned nanofiber scaffold, (ii) bFGF- releasing scaffold to enhance early cell survival and rapid angiogenesis, and (iii) the non-invasive monitoring of myocardial tissue oxygenation and cell engraftment in vivo. The outcome of this project will enable us to develop a novel cardiac patch for translation into a large animal clinical model of MI for repairing the damaged heart.