Injectable Decellularized Myocardial Matrix Hydrogel Mitigates Negative Left Ventricular Remodeling in a Chronic Myocardial Infarction Model

项目摘要 每年有超过75万美国人患有心肌梗死（MI）。MI是最常见的 全球范围内，心力衰竭（HF）是导致全球1/9死亡的原因。平均年龄 随着世界人口的增加，患有心力衰竭的患者数量预计将急剧增加。 在MI后急性炎症反应后，左心室（LV）壁将开始一连串事件， 最初旨在补偿损失心肌，但最终导致对心脏功能的有害影响 并促进HF恶化阶段的进展。负性左心室重构主要包括梗死 扩张、壁变薄、心肌细胞肥大和纤维化。目前，给予早期HF患者 旨在治疗症状的药物，而晚期患者必须采取更具侵入性的手术 例如LV辅助装置植入或全心脏移植。没有FDA批准的 HF患者可用的治疗方法，旨在促进梗死内的修复或再生， 阻止甚至逆转HF的进展。我们的实验室以前开发了一种组织特异性可注射水凝胶 来源于猪LV心肌的脱细胞细胞外基质，称为心肌基质（MM） 水凝胶，能够减轻MI亚急性模型中的负性LV重塑。这种水凝胶保留了 天然心肌中发现的蛋白质和糖胺聚糖（sGAG）的纳米结构。我们假设 MM水凝胶将能够通过以下方式在慢性MI的小动物大鼠模型中保持LV功能： 促进健康的心脏代谢、新血管形成，同时防止纤维化和肥大。 我们建议通过以下三个具体目标来研究这一假设： ·目的1：证明脱细胞心肌ECM在体内减轻负性LV的功效 慢性心肌梗死大鼠模型中的重构。 目的2：探讨脱细胞心肌细胞外基质（ECM）对特定细胞的作用机制 使用单细胞RNA测序在慢性心肌梗死的大鼠模型中的群体中进行。 显示MM水凝胶在慢性MI模型中的有效性将证明该材料的持续研究是合理的 在很大一部分患者群体中。了解材料对特定 慢性环境中的细胞群将扩大该领域的知识，并使我们能够确定 为这些患者提供更好的治疗目标。

Project Summary More than 750,000 Americans will suffer a myocardial infarction (MI) each year. MI is the most common cause for heart failure (HF) worldwide which is attributed to 1 in 9 deaths globally. With the average age of the world’s population increasing, the number of patients living with heart failure is expected to increase dramatically. After an acute inflammatory response post-MI, the left ventricle (LV) wall will begin a cascade of events that initially aim to compensate for lost cardiac muscle but eventually result in deleterious effects on cardiac function and promote progression through the worsening stages of HF. Negative LV remodeling consists mostly of infarct expansion, wall thinning, cardiomyocyte hypertrophy, and fibrosis. Currently, early stage HF patients are given medications that aim to treat the symptoms while late stage patients must resort to more invasive surgical procedures such as LV assist device implantation, or whole heart transplantation. There are no FDA-approved therapeutics available for patients living with HF that aims to promote repair or regeneration within the infarct to halt or even reverse the progression of HF. Our lab has previously developed a tissue-specific injectable hydrogel derived from decellularized extracellular matrices of porcine LV myocardium, called myocardial matrix (MM) hydrogel, capable of mitigating negative LV remodeling in a sub-acute model of MI. This hydrogel retains the nanostructure of, and proteins and glycosaminoglycans (sGAG’s) found in native myocardium. We hypothesize that the MM hydrogel will be able to preserve LV function in a small animal rat model of chronic MI by promoting healthy cardiac metabolism, neovascularization while preventing fibrosis and hypertrophy. We propose investigating this hypothesis through the following three specific aims: · Aim 1: To demonstrate efficacy of the decellularized myocardial ECM in vivo for mitigating negative LV remodeling in a rat model of chronic myocardial infarction. · Aim 2: To determine the mechanism of action of the decellularized myocardial ECM in specific cell populations in a rat model of chronic myocardial infarction using single cell RNA sequencing. Showing efficacy of the MM hydrogel in a chronic model of MI would justify the continued study of the material in a large portion of the patient population. Understanding the mechanism of action of the material on specific cell populations in a chronic environment would expand the knowledge of the field and allow us to determine better treatment targets for these patients in the future.