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.

基于细胞和生物学的治疗，旨在促进损伤后心肌恢复或预防进展 正在临床试验中进行开发和测试。然而，在这一领域开展工作的一个主要限制是， 对人类心肌细胞生物学的了解相对较少。提高我们的认识 心脏祖细胞功能的生物学特性是本提案的重点。分离出一小部分细胞 在培养中高度增殖，并表达关键的多能性 转录因子，并可刺激分化成内皮细胞，心肌细胞， 间充质谱系这些细胞表达⑶ 105（a.k.a. endoglin），其在以下传递中起作用： 转化生长因子β（TGFβ）和骨形态发生蛋白（BMP）信号传导。这些细胞还 表达不同水平的ERBB 1 -4受体酪氨酸激酶，其介导表皮细胞的作用。 表皮生长因子（EGF）家族，包括神经调节蛋白-1 β（NRG）。NRG和ERBB 1 -4对心脏 成人心脏的发育和维持。ERBB 1 -4在新鲜分离的前体细胞中的表达 细胞在个体之间变化，并且与可以被移植的高度增殖克隆的数量相关。 来自心肌活检。ERBB 2表达决定了这些祖细胞是否可以被 在用重组EGF或NRG-1刺激时，向内皮表型诱导。该公司- BMP家族共受体CD 105的表达，及其在血管生成和心脏发育中的作用， 表明这些细胞被该配体家族共同调节。该提案的中心假设是， ERBB 1 -4受体表达由BMP 9/CD 105决定，并调节细胞的活力、数量和能力。 祖细胞分化为内皮细胞和其他谱系。早期传代祖细胞的集合 在缅因州医学中心，从同意的受试者的心室心肌中分离出克隆 在过去的三年里。这些细胞中可变ERBB 2表达的功能意义将在下文中进行讨论。 在AIM 1心肌梗死后早期和晚期将细胞移植到小鼠心脏中的情况下进行了检查。 BMP 9/CD 105/Alk 1调控ERBB表达的机制及其功能意义将在以下几个方面进行探讨 在AIM 2中检查。从骨骼肌中可以分离出具有相似特征的高度增殖的克隆 以及心房心肌。从心房肌分离的祖细胞的程度， 骨骼肌与心室肌相似，将在AIM 3中进行检查。最终，这些发现 将提高我们对ERBB和CD 105如何调节心血管健康以及恢复的理解 并将为临床策略的设计提供信息，以增强心脏的恢复潜力。