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

通过心脏补片递送心外膜 FSTL1 和 CCND2 过表达心肌细胞进行心肌再肌化

基本信息

批准号：
10538614
负责人：
Vahid Serpooshan
金额：
$ 67.31万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/10538614
关键词：
3-Dimensional 3D Print Achievement Acute Acute myocardial infarction Adult Angiogenic Factor Apoptotic Arrhythmia BMP4 Biomechanics Biomedical Engineering Bioreactors Birth Blood Vessels CCND2 gene Cardiac Cardiac Myocytes Catheters Cell Cycle Cell Line Cell Proliferation Cell Surface Receptors Cells Characteristics Chemicals Chest Chronic Cicatrix Clinical Congestive Heart Failure Coupling Cues Devices Diagnostic Dilatation - action Echocardiography Electric Stimulation Encapsulated Endothelial Cells Engineering Engraftment Epicardium Face Family suidae Fibroblasts Follistatin Follistatin-Related Protein 1 Gadolinium Gelatin Generations Geometry Glycoproteins Heart Heart Injuries Heart failure Human Human Cell Line Hydrogels In Vitro Infarction Infusion procedures Injections Ischemia Label Left Left Ventricular Dysfunction Left Ventricular Remodeling Left ventricular structure Magnetic Resonance Imaging Maps Mediating Methacrylates Methods Molecular Mus Muscle Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Optics Patients Perfusion Pericardial body location Periodicity Pilot Projects Population Printing Process Proliferating Proto-Oncogene Proteins c-akt Public Health Reperfusion Therapy Reporting Resolution Risk Risk Reduction Role Shapes Signal Pathway Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stretching Surface Technology Testing Therapeutic Time Tissue Model Tissues Transplantation Treatment Protocols Vascularization Ventricular animal data bioink bioprinting cardioprotection cdc Genes cell type clinical application clinically relevant comparative efficacy design effectiveness evaluation endothelial stem cell glycosylation heart function implantation improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes ischemic cardiomyopathy ischemic injury knock-down meter minimally invasive mortality mouse model novel overexpression porcine model pre-clinical assessment prevent promoter receptor regeneration function repaired response scaffold

项目摘要

Title: 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 SA3a, we will assess the pre-clinical potential of bioengineered pre- vascularized muscle patch device in treating AMI in a pig model of ischemia-reperfusion. 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. SA3b, we will evaluate the effectiveness of the engineered patch for preventing the LV dilatation without inducing arrhythmogenic complications. The panoramic optical mapping and transmural electrical EP mapping whole heart will assess the electromechanical integration between the muscle patch constructs and recipient myocardium. The findings from these EP studies will guide the design of new generations of cell lines and patch constructs with improved EP characteristics, thereby reducing the risk of graft-associated arrhythmia

标题：心脏贴片FSTL1和CCND2的心脏贴片输送通过心肌弹性化过表达的心肌细胞项目摘要尽管接受了强化治疗方案，但经常患有严重急性心肌梗死（AMI）的患者最终以末期充血性心力衰竭（CHF）结束。从分子和细胞的角度来看，心力衰竭发生由于左心室收缩单位的损失：心肌细胞（CMS）。因此，促进心肌细胞的增殖和理解肌细胞细胞周期的调节剂可能会产生很大的影响关于心力衰竭的管理。在此提案中，我们试图开发3D生物工程的心肌结合功能性血管网络并概括一些关键微环境的构造天然心脏组织的提示。我们最近的研究确定了可以显着增强了成人CM的细胞周期重新进入。我们证明心外膜应用心脏贴片，女士follistatin oke-1（Fstl1）蛋白扩张和心力衰竭。我们最近报道了细胞周期基因CCND2（Cyclin d2）的过表达，诱导移植的人类诱导多能干细胞（HIPSC）衍生的CM的增殖。这个建议建立在我们最近的技术成就之上，使主要心脏细胞的铸造或生物打印高空间分辨率（20 µm）的水凝胶以制造3D灌注血管构建体。我们的中心假设是3D心脏结构，具有FSTL1和HIPSC-CCND2 CMS的女士可以协同作用雷神化缺血性心肌。我们在三个集成的特定目标（SAS）中检验了这一假设。在SA1中我们将利用铸造/生物打印的3D心脏组织模型来识别细胞和分子机制 FSTL1治疗在体外的基础肌细胞促生殖作用。在SA2中，我们将评估已确定的涉及FSTL1-CCND2 CM斑点效应的信号传导途径，以促进小鼠模型中的回弹化 Mi（急性和慢性）。在SA3A中，我们将评估生物工程前的临床前潜力血管化肌肉贴片装置在缺血 - 再灌注模型中治疗AMI中。我们将比较开放式胸部分娩与新型侵入性，基于导管的，心包递送FSTL1的功效和ccnd2 cm女士肌肉斑块到心外膜。 SA3B，我们将评估设计用于防止LV扩张的斑块，而无需诱发心律失常并发症。全景光学映射和透壁电气EP映射全心将评估机电整合在肌肉斑块构建体和受体心肌之间。这些EP研究的发现将指导新一代的细胞系和具有改进EP特征的贴片结构的设计，从而降低与移植相关心律不齐的风险