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.

最近发现心脏作为干细胞来源的发现为 自体细胞心肌成形术。这种心脏干细胞（CSC）已从啮齿动物的心脏中分离出来 以及人类手术标本。我们在隔离和扩展这些方面取得了重大进展 经皮的细胞获得了心内膜活检。在悬浮文化中生长时，CSC形成 自组织的球形簇显示了分化心肌细胞的几个特征。我们现在 建议在体外和体内继续对CSC和心球的功能表征。 了解CSC和Cardiopheres的电生理学可能会提供对心脏事件的见解 开发和修复，对于评估细胞移植的安全性和功效至关重要。这 应用旨在阐明在不同阶段的分子和电生理表型 分化。以前使用间充质干细胞和骨髓细胞的工作已经证明 心脏功能的改善而没有大量植入或注射细胞分化为 功能性心肌细胞。自体性心脏干细胞具有最高的植入潜力和 分化为功能性肌感。我们建议比较注射后的植入和分化 在心肌梗塞动物模型中的CSC或心圈。心际球可以根据他们的 三维结构，改善细胞植入，繁殖，生存和分化。临床试验 肌细胞（当前正在临床试验中的自体细胞类型）报告的室性较高的发生率很高 心律不齐可能继发于缺乏成肌细胞的电气整合。我们的初步数据揭示了 那个心脏干细胞表达CX43，能够与室中心肌细胞电偶联 文化。在这里，我们计划评估细胞在体外和IN中的电耦合和心律失常的潜力 体内使用光学映射，微电极记录和2光子显微镜。另一个重要功能 干细胞的能力是分泌对心脏功能具有有益作用的因素的能力。识别 干细胞分泌的因素可能允许损伤后立即直接递送生长因子 需要扩展细胞。我们将使用蛋白质组学技术来识别分泌的因素。 在临床翻译中，这项工作打开了改变心力衰竭治疗的可能性。