Electrophysiology and Cell Biology of Cardiac Stem Cells

心脏干细胞的电生理学和细胞生物学

• 批准号: 7391523
• 负责人: EDUARDO MARBAN
• 金额: $ 38.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391523
• 关键词: 3-Dimensional; Animal Model; Architecture; Autologous; Biological; Biopsy; Bone Marrow Cells; Cardiac; Cardiac Myocytes; Cardiomyoplasty; Cell Differentiation process; Cell Transplantation; Cells; Cellular biology; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Connexin 43; Coupling; Cues; Data; Development; Electrophysiology (science); Engraftment; Event; Gene Expression; Gene Expression Profile; Growth; Growth Factor; Heart; Heart failure; Human; In Vitro; Incidence; Injection of therapeutic agent; Injury; Ion Channel; Maps; Membrane; Mesenchymal Stem Cells; Methods; Microelectrodes; Microscopy; Molecular; Molecular Profiling; Muscle Cells; Myoblasts; Myocardial Infarction; Operative Surgical Procedures; Optics; Pattern; Phenotype; Photons; Property; Proteomics; Reporting; Rodent; Safety; Secondary to; Source; Specimen; Staging; Stem Cell Factor; Stem cell transplant; Stem cells; Suspension Culture; Techniques; Translations; Ventricular; Ventricular Arrhythmia; Work; cell type; clinical application; functional improvement; improved; in vivo; insight; interest; mouse model; novel; receptor; repaired

Recent discoveries identifying the heart as a source of stem cells have opened up new prospects for autologous cellular cardiomyoplasty. Such cardiac stem cells (CSCs) have been isolated from rodent hearts and from human surgical specimens. We have made substantial progress in isolating and expanding these cells from percutaneously obtained endomyocardial biopsies. When grown in suspension culture, CSCs form self-organizing spherical clusters that display several features of differentiating cardiomyocytes. We now propose to continue functional characterization of CSCs and cardiospheres in vitro and in vivo. Understanding the electrophysiology of CSCs and cardiospheres may provide insights into events in cardiac development and repair and is vital to assessing the safety and efficacy of cell transplantation. This application seeks to elucidate the molecular and electrophysiologic phenotype at different stages of differentiation. Previous work using mesenchymal stem cells and bone marrow cells has demonstrated improvement of cardiac function without significant engraftment or differentiation of the injected cells into functional cardiac myocytes. Autologous cardiac stem cells have the highest potential for engraftment and differentiation into functional myoctes. We propose to compare engraftment and differentiation after injection of CSCs or cardiospheres in an animal model of myocardial infarction. Cardiospheres may, by virtue of their 3-dimensional architecture, improve cell engraftment, multiplication, survival and differentiation. Clinical trials of myoblasts, (an autologous cell type currently in clinical trials) have reported a high incidence of ventricular arrhythmias probably secondary to lack of electrical integration of myoblasts. Our preliminary data reveals that cardiac stem cells express Cx43 and are capable of electrical coupling with ventricular myocytes in co- culture. Here, we plan to evaluate electrical coupling and arrhythmogenic potential of cells in vitro and in vivo, using optical mapping, microelectrode recordings and 2-photon microscopy. Another important feature of stem cells is their ability to secrete factors that have a beneficial effect on cardiac function. Identification of secreted factors by stem cells may permit direct delivery of growth factors immediately after injury obviating the need for cell expansion. We will use proteomic techniques to identify secreted factors.Given the potential of clinical translation, this work opens up the possibility of revolutionizing the treatment of heart failure.

最近的发现将心脏确定为干细胞的来源，为干细胞的研究开辟了新的前景。 自体细胞心肌成形术这种心脏干细胞（CSCs）已经从啮齿动物的心脏中分离出来 和人类手术标本。我们在隔离和扩大这些方面取得了实质性进展， 从子宫内膜肌层活检获得的细胞。当在悬浮培养中生长时， 自组织球形簇，显示分化心肌细胞的几个特征。我们现在 建议继续在体外和体内对CSC和心脏球进行功能表征。 了解CSC和心脏球的电生理学可以提供对心脏事件的见解， 它是细胞发育和修复的关键，对评估细胞移植的安全性和有效性至关重要。这 本申请试图阐明在不同阶段的分子和电生理表型， 分化先前使用间充质干细胞和骨髓细胞的研究已经证明， 心脏功能的改善，而注射的细胞没有显著的植入或分化成 功能性心肌细胞自体心脏干细胞具有最高的移植潜力， 分化为功能性肌细胞。我们建议比较移植和分化后注射 心肌梗死动物模型中的CSC或心脏球。由于它们的特性， 3-三维结构，改善细胞植入，增殖，存活和分化。临床试验 成肌细胞（目前在临床试验中的一种自体细胞类型）报告了心室肌纤维化的高发生率。 心律失常可能继发于成肌细胞缺乏电整合。我们的初步数据显示 心脏干细胞表达Cx43，并能够与心室肌细胞共电偶联， 文化在这里，我们计划在体外和体内评估细胞的电耦合和致突变潜力。 体内，使用光学映射，微电极记录和双光子显微镜。另一个重要特征 干细胞的最大优点是它们能够分泌对心脏功能有有益影响的因子。鉴定 干细胞分泌的因子可以允许在损伤后立即直接递送生长因子， 细胞扩张的需要。我们将使用蛋白质组学技术来鉴定分泌因子。 这项工作为心力衰竭的治疗带来了革命性的可能性。