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

HL131017 补充：通过心外膜 FSTL1 和 CCND2 过表达心肌细胞的心脏补片递送进行心肌再肌化

• 批准号: 10797360
• 负责人: Vahid Serpooshan
• 金额: $ 2.17万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797360
• 关键词: 3-Dimensional; 3D Print; Achievement; Acute; Acute myocardial infarction; Adult; BMP4; Biomechanics; Biomedical Engineering; Bioreactors; Birth; Blood Vessels; CCND2 gene; Cardiac; Cardiac Myocytes; Catheters; Cell Cycle; Cells; Chest; Chronic; Cicatrix; Clinical; Congestive Heart Failure; Creativeness; Cues; Devices; Dilatation - action; Electric Stimulation; Encapsulated; Endothelial Cells; Engineering; Engraftment; Epicardium; Family suidae; Fibroblasts; Follistatin; Follistatin-Related Protein 1; Fostering; Gadolinium; Gelatin; Generations; Glycoproteins; Health protection; Heart; Heart Injuries; Heart failure; Human; Human Cell Line; Hydrogels; In Vitro; Infarction; Ischemia; Left Ventricular Remodeling; Left ventricular structure; Mediating; Methacrylates; Mission; Molecular; Mus; Muscle; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Parents; Patients; Pericardial body location; Periodicity; Pilot Projects; Population; Preparation; Printing; Proliferating; Proto-Oncogene Proteins c-akt; Reperfusion Therapy; Reporting; Research; Resolution; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stretching; Technology; Testing; Therapeutic; Tissue Model; Tissues; Transplantation; Treatment Protocols; United States National Institutes of Health; Vascular Proliferation; Vascularization; bioink; bioprinting; cardioprotection; cdc Genes; cell type; comparative efficacy; effectiveness evaluation; endothelial stem cell; glycosylation; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; innovation; ischemic cardiomyopathy; ischemic injury; meter; minimally invasive; mortality; mouse model; novel; overexpression; porcine model; pre-clinical assessment; prevent; promoter; repaired; response; scaffold; time use; timeline

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.

标题： HL131017 补充：通过心外膜 FSTL1 的心脏补片递送进行心肌再肌化 和 CCND2 过表达心肌细胞 项目概要 尽管接受强化治疗方案，严重急性心肌梗死 (AMI) 患者仍经常出现以下情况： 最终出现终末期充血性心力衰竭（CHF）。从分子和细胞角度来看，心力衰竭 由于左心室收缩单位心肌细胞（CM）的丧失而发生。因此，推广 心肌细胞增殖和了解心肌细胞周期的调节因子可能会产生非常显着的影响 关于心力衰竭的治疗。在此提案中，我们寻求开发 3D 生物工程心肌 包含功能性血管网络并概括一些关键微环境的构建体 原生心脏组织的线索。我们最近的研究已经确定了主要的生物力学和分子线索，可以 显着增强成体 CM 的细胞周期重入。我们证明了心脏的心外膜应用 含有卵泡抑素样 1 (FSTL1) 蛋白的贴片可保护小鼠和猪心脏免受 AMI、左心室的影响 扩张和心力衰竭。我们最近报道了细胞周期基因 CCND2（细胞周期蛋白 D2）的过度表达， 诱导移植的人类诱导多能干细胞 (hiPSC) 衍生的 CM 的增殖。这个提议 以我们最近的技术成就为基础，能够对主要心肌细胞进行铸造或生物打印， 高空间分辨率 (20 µm) 的水凝胶可制造 3D 可灌注血管结构。我们的中央 假设充满 FSTL1 和 hiPSC-CCND2 CM 的 3D 心脏结构可以协同作用 使缺血的心肌重新肌化。我们在三个综合特定目标 (SA) 中测试了这一假设。在SA1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 FSTL1 治疗体外潜在的心肌细胞增殖作用。在 SA2 中，我们将评估已识别的 参与 FSTL1-CCND2 CM 贴片效应的信号通路，促进小鼠模型的肌再化 MI（急性和慢性）。在 SA3 中，我们将评估生物工程预血管化的临床前潜力 肌肉补片装置治疗猪缺血再灌注模型中的 AMI。心脏开胸分娩 补丁有仿制品。我们将比较开胸分娩与新型微创分娩的疗效， 基于导管的心包将满载 FSTL1 和 CCND2 CM 的肌肉补片输送至心外膜。研究结果 该项目将建立新一代个性化心脏补片设备，用于肌肉再造 心脏梗死后左心室重塑。