Molecular determinants of the fate of human heart mesenchymal progenitor cells

人心脏间充质祖细胞命运的分子决定因素

• 批准号: 10462585
• 负责人: Douglas B Sawyer
• 金额: $ 49.42万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462585
• 关键词: Acute; Adult; Animal Model; Area; Biological Response Modifier Therapy; Biology; Biopsy; Bone Morphogenetic Proteins; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiac development; Cardiomyopathies; Cell Fraction; Cell Proliferation; Cell Therapy; Cell Transplantation; Cells; Cellular biology; Characteristics; Chronic; Cicatrix; Clinical; Clinical Trials; Clone Cells; Collection; Consent; Data; Disease; EGFR gene; ENG gene; ERBB2 gene; Endoglin; Endothelial Cells; Endothelium; Epidermal Growth Factor; Exhibits; Family; Growth Factor; Heart; Heart Atrium; Heart Diseases; Heart Injuries; Heart failure; Human; Human Activities; Human Biology; Immunodeficient Mouse; In Vitro; Individual; Infarction; Injections; Knowledge; Left; Ligands; Maine; Maintenance; Mediating; Medical center; Mesenchymal; Mesenchymal Stem Cells; Methods; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardium; Neuregulins; Phenotype; Play; Population; Property; Protein Family; Receptor Protein-Tyrosine Kinases; Recombinant Epidermal Growth Factor; Regulation; Role; Series; Signal Transduction; Signaling Protein; Skeletal Muscle; Source; Stromal Cells; Structure; Testing; Time; Tissues; Transforming Growth Factor beta; Ventricular; Work; angiogenesis; base; bone morphogenetic protein receptors; cardiogenesis; cardiovascular health; cell replacement therapy; design; experimental study; heart cell; heart function; improved; in vivo; injury recovery; myocardial biopsy; pluripotency; prevent; progenitor; receptor; receptor expression; repaired; response; skeletal; stem cell function; stem cells; therapy design; transcription factor; transmission process

Cell and biology-based therapies designed to promote myocardial recovery after injury or prevent progression of heart failure are being developed and tested in clinical trials. However a major limitation to work in this area is the relatively poor understanding of the cell biology of the human myocardium. Improving our understanding of the biology of cardiac progenitor cells function is the focus of this proposal. A small fraction of cells isolated from the adult human ventricular myocardium are highly proliferative in culture, and express key pluripotency transcription factors, and can be stimulated to differentiate into endothelial, cardiac myocyte, and mesenchymal lineages. These cells express CD105 (a.k.a. endoglin), which functions in the transmission of transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling. These cells also express variable levels of ERBB1-4 receptor tyrosine kinases which mediate the effects of the epidermal growth factor (EGF) family including Neuregulin-1β (NRG). NRG and ERBB1-4 are critical for cardiac development and maintenance of the adult heart. The expression of ERBB1-4 in freshly isolated progenitor cells varies amongst individuals and is correlated to the quantity of highly proliferative clones that can be derived from myocardial biopsies. ERBB2 expression determines whether these progenitor cells can be induced toward an endothelial phenotype in response to stimulation with recombinant EGF or NRG-1. The co- expression of the BMP family co-receptor CD105, and its roles in angiogenesis and heart development, suggest co-regulation of these cells by this family of ligands. The central hypothesis of this proposal is that ERBB1-4 receptor expression is determined by BMP9/CD105 and regulates the viability, number, and ability of progenitor cells to differentiate to endothelial and other lineages. A collection of early passage progenitor cell clones isolated from ventricular myocardium in consenting subjects at Maine Medical Center has been created over the past 3 years. The functional significance of variable ERBB2 expression in these cells will be examined in the setting of cell transplant into mouse heart early and late after myocardial infarction in AIM 1. The mechanism by which BMP9/CD105/Alk1 regulates ERBB expression and its functional significance will be examined in AIM 2. Highly proliferative clones with similar characteristics can be isolated from skeletal muscle as well as atrial myocardium. The extent to which progenitor cells isolated from atrial myocardium and skeletal muscle are similar to the ventricular myocardium will be examined in AIM 3. Ultimately these findings will improve our understanding of how ERBB and CD105 regulate cardiovascular health as well as recovery from injury, and will inform the design of clinical strategies to enhance the restorative potential of the heart.

细胞和基于生物学的疗法旨在促进受伤后心肌恢复或预防进展 在临床试验中正在开发和测试心力衰竭。但是在这一领域工作的主要限制 是对人心肌细胞生物学的相对不良理解。提高我们的理解 心脏祖细胞功能的生物学是该提议的重点。一小部分分离的细胞 从成年人的人室心肌中，培养物高度增殖，并表达钥匙多质体 转录因子，可以刺激以区分内皮，心肌细胞和 间充质谱系。这些细胞表达CD105（又称内元），它在传播中起作用 转化生长因子β（TGFβ）和骨形态发生蛋白（BMP）信号传导。这些细胞也是 ERBB1-4受体酪氨酸激酶的表达可变水平，介导表皮的作用 生长因子（EGF）家族，包括Neuregulin-1β（NRG）。 NRG和ERBB1-4对于心脏至关重要 成人心脏的发展和维护。 ERBB1-4在新鲜分离的祖细胞中的表达 个体之间的细胞不同，并且与可以是高度增殖克隆的数量相关 源自心肌活检。 ERBB2表达确定这些祖细胞是否可以 通过重组EGF或NRG-1刺激诱导内皮表型。共同 BMP家族共受体CD105的表达及其在血管生成和心脏发育中的作用， 暗示该配体系列对这些细胞进行共同调节。该提议的核心假设是 ERBB1-4受体表达由BMP9/CD105确定，并调节可行性，数量和能力 祖细胞分化为内皮和其他线。早期通道祖细胞的集合 已经创建了从缅因州医疗中心同意对象中从心室心肌隔离的克隆 在过去的三年中。这些细胞中可变ERBB2表达的功能意义将是 在AIM 1中心肌梗死后的早期和晚期，在细胞移植到小鼠心脏中进行了检查。 BMP9/CD105/ALK1调节ERBB表达及其功能意义的机制将是 在AIM 2中检查。可以从骨骼肌肉中隔离具有相似特征的高度增殖克隆 以及心肌。祖细胞从心房心肌分离的程度和 骨骼肌类似于室心肌，将在AIM 3中检查。最终这些发现 将提高我们对ERBB和CD105如何调节心血管健康以及恢复的理解 受伤，并将告知临床策略的设计，以增强心脏的恢复潜力。