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

项目摘要 包括心肌梗死(MI)和进展为心力衰竭(HF)的缺血性心脏病是 是美国最大的死因。心肌细胞(CM)严重死亡和形成能力受限 心肌梗死后新的CM限制修复，导致坏死组织扩张和最终的心衰。目前，唯一的 终末期心力衰竭的现有治疗方法、心脏移植和左心辅助装置受到阻碍 供者心脏的可获得性、有限的医疗资源以及对患者生活质量的负面影响。至 改进现有医疗技术，从脱细胞提取的可注射心肌基质(MM)水凝胶 猪心脏细胞外基质已显示出良好的临床前结果，包括显著 改善动物心功能，增加心肌，减少负性左心室重构 MI后的模特。该项目的目标是确定新的CM编队是否在MI后增加 使用MM治疗可有助于改善心肌质量的观察疗效 并在治疗组中发挥作用。由于心脏的自然修复和CM周转有限，目前还存在争议 现有的细胞质雄性不育系和/或内源性祖细胞能否显著诱导新的CM形成 修复心脏的细胞。我们假设MM治疗诱导了新的CMS的形成。 现有的CMS和/或内源性祖细胞群体。利用DNA标记和转基因模型 为了跟踪体内的CM反应，设计了以下目标来确定CM的形成是否是一种 MM心脏修复的作用机制。 特异性目标1：研究心肌基质是否促进细胞的修复和/或增殖 心肌梗死后的心肌细胞 特定目标2：利用转基因小鼠模型确定心肌基质疗法 诱导预先存在的心肌细胞或内源性祖细胞促进新的 心肌细胞形成 特定目标#3：分析标记的心肌细胞的核内容和转录组，以提供 心肌基质治疗中新的心肌细胞形成的证据 这项拟议研究的长期目标是确定MM诱导的细胞机制 修复并利用这一认识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对抗慢性心脏疾病的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，这支持了这一使命 国家心肺血液研究所的目标。

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.