Supplement of HL131017: Myocardial remuscularization by cardiac patch delivery of epicardial FSTL1 and CCND2 overexpressing cardiomyocytes

职务名称： HL 131017的补充：通过心脏补片输送心外膜FSTL 1进行心肌肌重建 和CCND 2过表达的心肌细胞 项目摘要 尽管接受了强化治疗方案，但严重急性心肌梗死（AMI）患者通常 最终导致充血性心力衰竭（CHF）。从分子和细胞的角度来看，心力衰竭 由于左心室的收缩单位：心肌细胞（CM）的丧失而发生。因此，促进 肌细胞增殖和了解肌细胞细胞周期的调节因子可能会产生非常重要的影响 心力衰竭的治疗在这项提案中，我们寻求开发3D生物工程心肌， 构建了一个功能性的血管网络，并概括了一些关键的微环境， 天然心脏组织的线索我们最近的研究已经确定了主要的生物力学和分子线索， 显著增强成年CM细胞周期再进入。我们证明了心外膜应用心脏 载有卵泡抑素样1（FSTL 1）蛋白的贴片保护小鼠和猪心脏免受AMI、左心室 扩张和心力衰竭我们最近报道过表达细胞周期基因CCND 2（细胞周期蛋白D2）， 诱导移植的人诱导多能干细胞（hiPSC）衍生的CM的增殖。这项建议 基于我们最近的技术成就，能够铸造或生物打印主要心脏细胞， 水凝胶以高空间分辨率（20 μm）制造3D可灌注血管结构。我们的中央 一种假设是，载有FSTL 1和hiPSC-CCND 2 CM的3D心脏构建体可以协同地 使缺血的心肌肌化。我们测试这一假设在三个综合的具体目标（SA）。在SA 1中， 我们将利用我们的铸造/生物打印3D心脏组织模型来识别细胞和分子机制， FSTL 1处理在体外的潜在肌细胞促增殖作用。在SA 2中，我们将评估已确定的 参与FSTL 1-CCND 2 CM-贴片效应的信号通路促进小鼠模型中的肌肉化 急性和慢性心肌梗死（MI）。在SA 3中，我们将评估生物工程预血管化的临床前潜力， 肌补片装置治疗猪急性心肌梗死缺血再灌注模型的研究。心脏病的开胸分娩 补丁有仿制品。我们将比较开胸分娩与一种新型微创， 将FSTL 1和CCND 2 CM负载的肌肉补片基于导管、心包递送至心外膜。这些发现 该项目的一部分将建立新一代个性化心脏补片装置，用于 心肌梗死后左心室重构。

Title: Supplement of HL131017: Myocardial remuscularization by cardiac patch delivery of epicardial FSTL1 and CCND2 overexpressing cardiomyocytes Project Summary Despite undergoing intensive treatment regimens, patients with severe acute myocardial infarction (AMI) often end up with end stage congestive heart failure (CHF). From the molecular and cellular perspective, heart failure occurs due to the loss of the contractile unit of the left ventricle: cardiomyocytes (CMs). Therefore, promotion of myocyte proliferation and understanding the regulators of myocyte cell cycle could have highly significant impact on the management of heart failure. In this proposal, we seek to develop 3D bioengineered cardiac muscle constructs that incorporate a functional vascular network and recapitulate some of the key microenvironmental cues of native heart tissue. Our recent studies have identified main biomechanical and molecular cues that can significantly enhance cell cycle re-entry of adult CMs. We demonstrated that epicardial application of a cardiac patch, laden with follistatin like-1 (FSTL1) protein, protected the mouse and pig heart against AMI, left ventricle dilatation, and heart failure. We recently reported that overexpression of a cell cycle gene, CCND2 (cyclin D2), induces proliferation of transplanted human induced pluripotent stem cell (hiPSC) derived-CMs. This proposal builds upon our recent technological achievements, enabling cast or bioprinting of major cardiac cells and hydrogels at high spatial resolution (20 µm) to fabricate 3D perfusable vascular constructs. Our central hypothesis is that 3D cardiac constructs, laden with FSTL1 and hiPSC-CCND2 CMs, can synergistically remuscularize ischemic myocardium. We test this hypothesis in three integrated Specific Aims (SAs). In SA1, we will utilize our cast/bioprinted 3D cardiac tissue models to identify the cellular and molecular mechanisms underlying myocyte pro-proliferative effect of FSTL1 treatment in vitro. In SA2, we will assess the identified signaling pathways, involved in FSTL1-CCND2 CM-patch effect, to promote remuscularization in mouse model of MI (both acute and chronic). In SA3, we will assess the pre-clinical potential of bioengineered pre-vascularized muscle patch device in treating AMI in a pig model of ischemia-reperfusion. The open chest delivery of cardiac patches have imitations. We will compare the efficacy of open chest delivery versus a novel minimally invasive, catheter-based, pericardial delivery of FSTL1 and CCND2 CM laden muscle patch to the epicardium. The findings of this project will establish a novel generation of personalized cardiac patch devices for remuscularization of heart with postinfarction LV remodeling.