Micro-RNA and Differentitation of Cardiac Progenitor Cells

Micro-RNA 与心脏祖细胞的分化

• 批准号: 7837491
• 负责人: Toru Hosoda
• 金额: $ 34.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837491
• 关键词: Adherens Junction; Adult; Affect; Area; Attenuated; Autologous; Biological; Biological Preservation; Bone Marrow; Cadherins; Calcium; Cardiac; Cardiac Myocytes; Cell Adhesion Molecules; Cell Communication; Cell Differentiation process; Cell division; Cells; Characteristics; Clinical; Commit; Connexin 43; Contractile Proteins; Coupled; Data; Defect; Differentiation and Growth; Distant; E-Cadherin; Environment; Fibroblasts; Functional RNA; Gap Junctions; Gene Expression; Gene Silencing; Gene Targeting; Generations; Genes; Growth Factor; Heart; Heart failure; Homeostasis; Human; Hypertrophy; Infarction; Injection of therapeutic agent; Left; Maintenance; Mediating; MicroRNAs; Modality; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; N-Cadherin; Natural regeneration; Neonatal; Organ; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Property; Proteins; Recovery; Role; Signal Transduction; Skin; Small RNA; Space Perception; Stem cells; Supporting Cell; Testing; Time; Undifferentiated; Ventricular; Work; base; cell behavior; cell growth; cytokine; fetal; gap junction channel; implantation; in vivo; interest; member; migration; muscle form; novel; novel strategies; overexpression; primitive cell; progenitor; programs; public health relevance; repaired; restoration; small molecule; stem cell niche; stemness; transdifferentiation

DESCRIPTION (provided by applicant): Myocardial regeneration after infarction mediated by injection of autologous cardiac progenitor cells (CPCs) or local activation of resident CPCs by growth factors results in a significant recovery of ventricular muscle mass. However, the regenerated myocytes are small and have fetal-neonatal characteristics. These cells tend not to increase in size over time and in the majority of cases fail to attain the properties of adult fully mature myocytes. In contrast, the occasional migration of CPCs from the border zone to the remote myocardium results in the formation of myocytes which are indistinguishable from preexisting adjacent cells. This difference in CPC behavior suggests that the differentiation of CPCs may depend on surrounding cells which are connected through gap junctions to the primitive cells. MicroRNAs (miRs) which are emerging as an unexpected mechanism of control of progenitor cell fate are small RNAs that have the ability to traverse gap junctions. In this application I am raising the hypothesis that miR-499 that is highly expressed in cardiomyocytes and minimally present or absent in undifferentiated human CPCs may be involved in the maintenance of the terminally differentiated state of myocytes and may translocate to neighboring CPCs initiating their differentiation. Preliminary data demonstrate that miR-499 translocate from donor cells to neighboring human CPCs through gap junctions and the accumulation of miR-499 in CPCs is coupled with a decreased expression of the target genes, Sox6 and Rod1. The possibility is advanced that SoxD proteins, Sox5 and Sox6, negatively modulates the function of the members of the SoxF group of proteins inhibiting cardiomyogenesis. Sox5 and Sox6 may oppose the activation of the Wnt-2-catenin pathway which may condition late differentiation of human CPCs into cardiomyocytes. Based on this hypothesis, in vivo studies will be conducted to demonstrate whether overexpression of miR-499 in human CPCs promotes myocyte differentiation in the infarcted heart. PUBLIC HEALTH RELEVANCE: One of the major problems in cardiac repair is the lack of maturation of the newly formed cardiomyocytes. The work proposed here may overcome this limitation and offer a novel strategy for the treatment of the infarcted heart. If successful, this work may have important clinical implications for the management of human heart failure.

描述（由申请人提供）：通过注射自体心脏祖细胞（CPC）介导的梗塞后心肌再生或通过生长因子局部激活居民CPC，从而导致心室肌肉质量显着恢复。但是，再生的肌细胞很小，具有胎儿 - 炎的特征。这些细胞往往不会随着时间的流逝而增加，并且在大多数情况下，这些细胞无法获得成人完全成熟的肌细胞的特性。相比之下，CPC偶尔从边界区迁移到远程心肌会导致形成的心肌细胞，这些肌细胞与相邻的相邻细胞是无法区分的。 CPC行为的这种差异表明，CPC的分化可能取决于周围的细胞，这些细胞是通过间隙连接到原始细胞连接的。作为祖细胞命运控制的意外机制的microRNA（miR）是具有横穿差距连接的能力的小RNA。在此应用中，我提出了这样一个假设，即在心肌细胞中高度表达的miR-499在未分化的人CPC中最少或不存在或不存在的miR-499可能参与了肌细胞的终端分化状态，并可能转化为邻近的CPC，从而启动其分化。初步数据表明，miR-499通过间隙连接从供体细胞转移到邻近的人CPC，而miR-499在CPC中的积累与靶基因SOX6和ROD1的表达降低相结合。可能性是，Soxd蛋白Sox5和Sox6的可能性会负责调节抑制心肌生成的Soxf蛋白的成员的功能。 Sox5和Sox6可能会反对Wnt-2-Catenin途径的激活，该途径可能调节人CPC的晚分化为心肌细胞。基于这一假设，将进行体内研究，以证明人CPC中miR-499的过表达是否促进了梗塞心脏中的心肌细胞分化。公共卫生相关性：心脏修复的主要问题之一是新形成的心肌细胞缺乏成熟。这里提出的工作可能会克服这一局限性，并为治疗梗塞心脏的治疗提供了新的策略。如果成功，这项工作可能对人类心力衰竭的管理具有重要的临床意义。