Investigating Whether Myocardial Matrix Therapy Induces New Cardiomyocyte Formation Following Myocardial Infarction

项目摘要 缺血性心脏病包括心肌梗死（MI）和进展为心力衰竭（HF）， 美国的主要死因。显著心肌细胞（CM）死亡和形成能力有限 MI后新CM限制修复，导致坏死组织扩张和最终HF。目前，唯一 终末期心力衰竭的有效治疗、心脏移植和左心室辅助装置受到阻碍， 由于供体心脏的可用性、有限的医疗资源和对患者生活质量的负面影响，到 改进现有医疗技术，可注射的心肌基质（MM）水凝胶衍生自脱细胞的 猪心脏细胞外基质已经显示出有希望的临床前结果， 改善动物的心功能，增加心肌，减少左心室负性重塑 MI后模型。本项目的目标是确定MI后是否出现新CM形成的增加 MM治疗可能有助于观察到的改善心肌质量的治疗结局 并在治疗组中发挥作用。由于心脏具有有限的天然修复和CM周转， 是否可以从预先存在的CM和/或内源性祖细胞显著诱导新的CM形成 修复心脏的细胞我们假设MM治疗诱导了新CM的形成， 现有的CM和/或内源性祖细胞群体。利用DNA标记和转基因模型 为了跟踪CM在体内的反应，设计了以下目标来确定CM的形成是否是 促进MM心脏修复的机制。 心肌特异性目标1：研究心肌基质是否会增加心肌细胞的DNA修复和/或增殖。 心肌梗死后心肌细胞 具体目标2：利用转基因小鼠模型确定心肌基质治疗是否 诱导预先存在的心肌细胞或内源性祖细胞， 心肌细胞形成 具体目标#3：分析标记的心肌细胞的细胞核含量和转录组，以提供 心肌基质治疗形成新心肌细胞的证据 这项研究的长期目标是确定MM诱导的细胞机制。 修复并利用这种理解来创造更完整的心血管疾病生物材料治疗方法。 这个项目将促进我们对细胞机制的基本理解， 组织疾病，并有助于改善国家的心血管健康，这支持了使命 国家心脏，肺和血液研究所的目标。

Project Summary Ischemic heart disease encompassing myocardial infarction (MI) and progression to heart failure (HF) is the leading cause of death in the United States. Significant cardiomyocyte (CM) death and limited ability to form new CM post-MI restricts repair leading to necrotic tissue expansion and eventual HF. Currently, the only available treatments for end-stage heart failure, heart transplant and left ventricular assist devices, are hindered by availability of donor hearts, limited medical resources and negative impacts on patients’ quality of life. To improve available medical technology, injectable myocardial matrix (MM) hydrogels derived from decellularized porcine cardiac extracellular matrix have demonstrated promising pre-clinical results including significantly improved cardiac function, increased cardiac muscle and reduced negative left ventricular remodeling in animal models post-MI. The goal of this project is to determine whether increases in new CM formation occurs post-MI with MM therapy that could contribute to the observed therapeutic outcomes of improved cardiac muscle mass and function in treated groups. Since the heart has limited native repair and CM turnover, it is currently debated whether new CM formation can be significantly induced from pre-existing CMs and/or endogenous progenitor cells to repair the heart. We hypothesize that MM treatment induces formation of new CMs from pre- existing CMs and/or endogenous progenitor cell populations. Utilizing DNA labels and transgenic models to track CM response in vivo, the following aims are designed to determine whether CM formation is a contributing mechanism to MM cardiac repair.  Specific Aim #1: Investigate whether myocardial matrix increases DNA repair and/or proliferation of cardiomyocytes post-myocardial infarction  Specific Aim #2: Utilize transgenic mouse models to determine whether myocardial matrix therapy induces pre-existing cardiomyocytes or endogenous progenitor cells to contribute to new cardiomyocyte formation  Specific Aim #3: Analyze nuclei content and transcriptome of labeled cardiomyocytes to provide evidence of new cardiomyocyte formation from myocardial matrix therapy The long term objective of this proposed research is to determine cellular mechanisms involved in MM induced repair and use this understanding to create more complete biomaterial treatments for cardiovascular diseases. This project will advance our basic understanding of cellular mechanisms that can combat chronic cardiac tissue diseases and contribute to improving the nation’s cardiovascular health, which supports the mission goals of the National Heart, Lung and Blood Institute.