Cardiomyocyte Differentiation Regulates Cardiac Function

心肌细胞分化调节心脏功能

• 批准号: 8584311
• 负责人: Mark A PERRELLA
• 金额: $ 41.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-02 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584311
• 关键词: Accounting; Actins; Adult; Affect; American; Appearance; Area; Birth; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Count; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cessation of life; Chest; Commit; Cytoskeleton; Data; Defect; Development; Diagnosis; Dilated Cardiomyopathy; Disease; Embryo; Family; Family member; Functional disorder; Generations; Genes; Goals; Heart; Heart failure; Incidence; Injury; Investigation; Laboratories; Left atrial structure; Length; Mammals; Mus; Muscle Cells; Mutation; Myocardial; Myocardium; Myosin Light Chain Kinase; Natural regeneration; Neonatal Mortality; Newborn Infant; Organ; Pathway interactions; Phenotype; Process; Protein Family; Protein Isoforms; Protein-Serine-Threonine Kinases; RNA Splicing; Regulation; Research; Right atrial structure; Role; Signal Pathway; Site; Stem cells; Stress; Striated Muscles; Structure; Therapeutic; Thick; Tissues; Transmission Electron Microscopy; United States; base; cardiogenesis; cell type; constriction; experience; heart function; injured; injury and repair; insight; interest; member; mouse model; mutant; obscurin-MLCK; overexpression; postnatal; pressure; promoter; response; response to injury; stem

PROJECT SUMMARY / ABSTRACT: Different from many organs, the heart previously was felt to be a terminally differentiated, postmitotic organ. This led to the assumption that the heart contained a fixed number of cells postnatally, and that if injury led to myocyte death, the myocardium would need to maintain its functional role with a reduced number of cells. While striated muscle cells of cardiac origin undergo terminal differentiation shortly after birth in mammals, it has been shown that myocardial regeneration occurs following injury. This concept led to an interest in the potential of stem/progenitor cells in the heart. Endogenous cardiac progenitor cells (CPCs) are capable of limited myocardial regeneration at sites of injury, however the therapeutic potential of exogenously administered progenitor cells has been an intense area of investigation, as heart failure due to myocardial injury remains a difficult and deadly problem for millions of Americans. Thus, a major objective of this application is to further understand pathways responsible for the fate of CPCs (both during development and postnatally into adulthood), and to understand the ability of these progenitor cells to divide and differentiation into functional cardiomyocytes. Myosin light chain kinases (MLCK) are a family of proteins that are important for myocyte function. One member of this family is the striated preferentially expressed gene (Speg). The Speg locus generates four different gene isoforms, with Speg¿ and Speg¿ being expressed preferentially in striated muscle (including muscle of cardiac origin). Speg¿ and Speg¿ share homology with MLCK family members, and along with obscurin-MLCK, are unique members of the MLCK family as they contain two tandemly arranged serine/threonine kinase (MLCK) domains. Prior investigations in our laboratory revealed that Speg isoforms (particularly Speg¿) are markers of striated muscle differentiation. However, the functional significance of Speg isoforms was yet to be elucidated. We disrupted the Speg gene locus in mice, and revealed that homozygous mutant (Speg-/-) hearts began to enlarge by 16.5 days post-coitum (dpc), and by 18.5 dpc showed a marked dilation of right and left atria and ventricles. These dilated Speg mutant hearts demonstrated poor function, and a phenotype consistent with a dilated cardiomyopathy. Speg-/- mice also experienced significant neonatal mortality. Interestingly, the hearts of Speg-/- mice showed a reduced number of cells per mm3 of tissue compared with Speg+/+ mice, and a less differentiated appearance by transmission electron microscopy (EM), suggesting an alteration in the development of cardiac parenchymal cells. The overall goal of the application is to elucidate the role of Speg in the fate and differentiation of CPCs into functional cardiomyocytes, and to ascertain the importance of Speg in cardiac injury, repair, and function. To achieve this goal, we propose the following Aims: 1) investigate the role of Speg in CPC fate, commitment to the cardiomyocyte lineage, and cardiomyocyte differentiation; 2) decipher the mechanisms responsible for the development of cardiac dysfunction in the absence of Speg; & 3) determine the importance of Speg during cardiac injury (pressure overload) in adult mice.

项目摘要 /摘要：与许多器官不同，以前的心被认为是 末端分化后的有丝分裂器官。这导致假设心脏包含固定数量的 出现后细胞，如果受伤会导致心肌死亡，则需要保持其功能 细胞数量减少的作用。而横纹的心脏来源肌肉细胞经历终末分化 哺乳动物出生后不久，已经表明心肌再生发生在受伤后。 概念引起了对心脏中茎/祖细胞潜力的兴趣。内源性心脏祖细胞 细胞（CPC）能够在损伤部位有限的心肌再生，但是治疗潜力 外源给药的祖细胞的研究一直是一个强烈的研究领域，因为 对于数百万美国人来说，心肌损伤仍然是一个困难而致命的问题。这是一个主要目标 应用是为了进一步了解负责CPC命运的途径（无论在开发期间和 产后到成年），并了解这些祖细胞分裂和分化为 功能性心肌细胞。肌球蛋白轻链激酶（MLCK）是一个对蛋白质的家族，对 心肌功能。该家族的一位成员是曲折的优先表达基因（SPEG）。 SPEG 基因座产生四个不同的基因同工型，而Speg？和Speg？更优选地表达 肌肉（包括心脏起源的肌肉）。 Speg¿和Speg¿与MLCK家庭成员分享同源性，以及 除了掩盖蛋白MLCK外，MLCK家族的独特成员，因为它们包含两个串联布置 丝氨酸/苏氨酸激酶（MLCK）结构域。我们实验室的先前调查表明，SPEG同工型 （尤其是SPEG？）是条纹肌肉分化的标记。但是，SPEG的功能意义 同工型尚未阐明。我们破坏了小鼠的SPEG基因基因座，并揭示了纯合子 突变体（speg - / - ）心脏开始在涂层后16.5天扩大（DPC），而在18.5 dpc中显示出明显的明显 左右心室和心室的扩张。这些扩张的Speg突变心表现出功能不佳，并且 与扩张性心肌病一致的表型。 SPEG - / - 小鼠也经历了明显的新生儿 死亡。有趣的是，SPEG - / - 小鼠的心脏显示每MM3的细胞数量减少 与SPEG+/+小鼠相比，透射电子显微镜（EM）的外观较小， 表明心脏实质细胞的发展发生了改变。应用程序的总体目标是 阐明SPEG在CPC中的命运和分化为功能性心肌细胞中的作用，并确定 SPEG在心脏损伤，修复和功能中的重要性。为了实现这一目标，我们提出以下内容 目的：1）研究SPEG在CPC命运，对心肌细胞谱系的承诺和心肌细胞的作用 分化； 2）破译负责心脏功能障碍发展的机制 缺乏SPEG； ＆3）确定成年小鼠心脏损伤期间SPEG的重要性。

项目成果

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero.

通过在子宫内施用心脏祖细胞来挽救小鼠新生心脏功能障碍

• DOI: 10.1038/ncomms9825
• 发表时间: 2015-11-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Liu X;Hall SRR;Wang Z;Huang H;Ghanta S;Di Sante M;Leri A;Anversa P;Perrella MA
• 通讯作者: Perrella MA

Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure.

• DOI: 10.3389/fphys.2018.00863
• 发表时间: 2018
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Shu C;Huang H;Xu Y;Rota M;Sorrentino A;Peng Y;Padera RF Jr;Huntoon V;Agrawal PB;Liu X;Perrella MA
• 通讯作者: Perrella MA