Enhancement of Cardiac Cell therapy by reintroduction of developmental signaling

通过重新引入发育信号增强心脏细胞治疗

• 批准号: 9218489
• 负责人: Mohsin Khan
• 金额: $ 39万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218489
• 关键词: Address; Adult; Age; Age of Onset; American; Autologous; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle Progression; Cell Therapy; Cell Transplants; Cells; Cicatrix; Clinic; Clinical; Clinical Trials; Coronary heart disease; Data; Development; Disease; Diving; Embryo; Fetal Heart; Goals; Growth; Harvest; Heart; Heart Diseases; Heart failure; Human; Injury; Kinetics; Link; Maintenance; Mediating; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Morphology; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Neonatal; Onset of illness; Pathologic; Pathology; Patients; Performance; Prevalence; Process; Property; Publishing; Pump; Regenerative Medicine; Regenerative response; Regulation; Research; Rest; Role; Safety; Signal Transduction; Site; Stem cells; Structure; Testing; Therapeutic; Tissues; Treatment Efficacy; United States; adult stem cell; base; burden of illness; cardiac repair; design; exosome; fetal; heart function; improved; loss of function; mortality; myocardial damage; novel; older patient; repaired; response; therapeutic evaluation; tissue repair

Project summary Ischemic heart disease (IHD) is a major cause of morbidity and mortality in the US. Adult heart is largely dormant, designed primarily to perform pump function and responding to pathological challenge by limited myocyte turnover with development of scar tissue at the site of injury. Incredibly, cardiac tissue during developmental stages consists of actively diving cardiomyocytes and is able to resolve injury by formation of new tissue. The fundamental question is whether adult heart can be somehow driven into a developmental signaling state restoring cellular replacement without compromising pump function. Cardiac progenitor cell- based (CPC) applications have been widely used to resurrect myocardial repair processes and have moved into clinic but are limited due to underperformance of the donated cells. In most cases, CPCs are harvested from elderly patients with an adverse cardiac tissue morphology including host of clinical features reducing therapeutic efficacy of the cells and their cell-free agents such as exosomes. Interestingly, CPCs are known to possess incredible growth and repair properties during fetal and neonatal cardiac stages and understanding unique signaling hubs regulating CPC performance during development may open up a novel avenue for enhancement of CPC therapy. Ideally changing cardiac microenvironment to resemble a developmental cardiac tissue may offer a powerful way to restore lost cardiac repair ability. Our preliminary data indicates miR-294 signaling axis enhances cardiac performance including core CPC function mediated by its downstream target Lin28a. Therefore, we hypothesize that reintroduction of developmental miR-294-Lin28a signaling axis in CPCs will promote CPC properties reminiscent of more primitive developmental stage where the heart can better repair itself. Our goal is to enhance CPC therapy including the potency of cell-free agents such as exosomes by induction of developmental signaling to repair the heart after myocardial damage. We will extend these studies to develop a therapeutic strategy on miR294-Lin28a based modification of human heart derived CPCs and their exosomes that enhances cardiac structure and function after injury. Enhancement of cardiac cell therapy by reintroduction of developmental signaling provides a new direction for CPC based cell therapeutics and treatment of heart failure.

项目摘要 缺血性心脏病（IHD）是美国发病率和死亡率的主要原因。成人心脏 主要是休眠的，主要是为了执行泵功能和响应病理性的 受到有限的肌细胞更新的挑战，在损伤部位形成瘢痕组织。 令人难以置信的是，发育阶段的心脏组织由活跃的潜水 心肌细胞，并且能够通过形成新组织来解决损伤。根本 问题是成年人的心脏是否能以某种方式进入发育信号状态 在不损害泵功能的情况下恢复细胞替换。心脏祖细胞- 基于CPC的应用已广泛用于恢复心肌修复过程， 已经进入临床，但由于捐献细胞的性能不佳而受到限制。在大多数 例，CPC从具有不良心脏组织形态的老年患者中获得 包括降低细胞治疗功效的临床特征的宿主及其无细胞 如exosomes。有趣的是，众所周知，CPC拥有令人难以置信的增长， 在胎儿和新生儿心脏阶段的修复特性和理解独特的信号传导 在发展过程中规范中国共产党绩效的中心可能会开辟一条新的途径， 加强CPC治疗。理想地改变心脏微环境， 发育中的心脏组织可能为恢复失去的心脏修复能力提供强有力的方法。我们 初步数据表明miR-294信号传导轴增强心脏性能，包括核心 CPC功能由其下游靶点Lin 28 a介导。因此，我们假设 在CPC中重新引入发育中的miR-294-Lin 28 a信号传导轴将促进CPC 这些特性让人想起更原始的发育阶段，在这个阶段，心脏可以更好地修复 本身我们的目标是增强CPC治疗，包括无细胞药物的效力， 外泌体通过诱导发育信号来修复心肌损伤后的心脏。 我们将扩展这些研究以开发基于miR 294-Lin 28 a的治疗策略。 增强心脏结构的人心脏来源的CPC及其外来体的修饰 受伤后的功能通过重新引入心肌细胞来增强心脏细胞治疗 发育信号传导为基于CPC的细胞治疗提供了新的方向， 心力衰竭的治疗