Molecular determinants of the fate of human heart mesenchymal progenitor cells

旨在促进损伤后心肌恢复或防止进展的细胞和生物疗法 正在开发心力衰竭的治疗方法并在临床试验中进行测试。然而，在这一领域工作的一个主要限制 对人类心肌细胞生物学的认识相对较差。提高我们的理解 心脏祖细胞功能的生物学研究是这一提议的重点。分离出的一小部分细胞 成人心肌细胞在培养中高度增殖，并表现出关键的多能性。 转录因子，并可被刺激分化为内皮细胞、心肌细胞和 间充质血统。这些细胞表达CD105(又名Endoglin)，它在传递 转化生长因子β和骨形态发生蛋白信号转导。这些细胞还 表达不同水平的ErbB1-4受体酪氨酸激酶，介导表皮的作用 生长因子家族包括神经调节蛋白-1β(NRG)。NRG和ErbB1-4对心脏 成人心脏的发育和维护。ErbB1-4在新鲜分离的祖细胞中的表达 细胞因个体而异，并与高度增殖的克隆的数量有关 取自心肌活组织检查。ERBB2的表达决定了这些祖细胞是否可以 在重组EGF或NRG-1刺激下，向内皮表型诱导。联席- 骨形态发生蛋白家族共受体CD105的表达及其在血管生成和心脏发育中的作用 建议通过这个配体家族共同调节这些细胞。这项提议的中心假设是 ErbB1-4受体的表达由BMP9/CD105决定，并调节细胞的活性、数量和能力。 祖细胞分化为内皮细胞和其他谱系。一批早期传代祖细胞 从缅因州医学中心自愿受试者的心室肌分离出克隆 在过去的3年里。在这些细胞中可变ERBB2表达的功能意义将是 在心肌梗死后早期和晚期心肌梗死小鼠心脏内细胞移植的设置中进行检测。 BMP9/CD105/Alk1调节ERBB表达的机制及其功能意义如下 目的2.可以从骨骼肌中分离出具有相似特征的高增殖克隆 以及心房肌层。从心房肌中分离出的祖细胞和 骨骼肌类似于心室肌，将在目标3中进行检查。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康复的理解 保护心脏免受伤害，并将为临床策略的设计提供信息，以增强心脏的恢复潜力。

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.