Epicardial progenitors in the developing and postnatal heart

发育中和出生后心脏中的心外膜祖细胞

• 批准号: 8704989
• 负责人: William Tswenching Pu
• 金额: $ 43.91万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704989
• 关键词: Adult; Animals; Blood Vessels; Blood capillaries; Bone Marrow; Cardiac; Cardiac Myocytes; Cells; Clinical; Clinical Research; Coronary; Data; Development; EFRAC; Endothelial Cells; Epicardium; Epithelium; Fetal Heart; Fibroblasts; Genes; Genetic; Goals; Growth; Heart; Heart Diseases; Heart Injuries; Heart failure; Homeostasis; IGF1 gene; Infarction; Knowledge; Label; Lead; MAP Kinase Gene; Mesenchymal; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardium; Myofibroblast; NRG1 gene; Natural regeneration; Nephroblastoma; Outcome; Paracrine Communication; Pathway interactions; Perfusion; Population; Pre-Clinical Model; Process; Property; Regulation; Research Project Grants; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stem cells; Technology; Testing; Therapeutic; Time; Translating; Translations; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular blood supply; WT1 gene; Wilms Tumor Suppressor 1; capillary; cardiac regeneration; cardiac repair; cell behavior; density; design; effective therapy; epithelial to mesenchymal transition; fetal; improved; injured; insight; loss of function; mortality; novel; novel therapeutics; paracrine; postnatal; progenitor; public health relevance; regenerative; repaired; research study; response to injury; small molecule; thymosin beta(4); transcription factor; vasculogenesis

DESCRIPTION (provided by applicant): Heart failure is the leading cause of morbidity and mortality world-wide. Current heart failure treatments are not effective in enhancing myocardial repair or regenerating lost heart muscle. Improving myocardial repair after myocardial infarction will require enhancing vascular supply to regions with marginal perfusion and stimulating myocardial regeneration through formation of new cardiomyocytes and supporting vasculature. The epicardium, a polarized epithelium covering the heart, is an essential regulator of fetal myocardial growth and coronary vasculogenesis. Epicardium and myocardium engage in elaborate paracrine signaling to regulate each other's development. Furthermore, epicardial cells undergo epithelial to mesenchymal transition (EMT), generating epicardium-derived mesenchymal cells (EPDCs) that migrate into the heart and differentiate into fibroblasts, vascular smooth muscle cells, endothelial cells, and potentially cardiomyocytes. In the adult heart, epicardium is an important modulator of the myocardial injury response, and recent studies indicate that the developmental properties of epicardium may be harnessed for therapeutic regeneration. Our preliminary data show that chemically modified mRNA (m*RNA) drives transient, high level paracrine factor expression in the heart. VEGF-A m*RNA, delivered once at the time of experimental myocardial infarction (MI), enhanced capillary density, reduced infarct size, improved ejection fraction, and enhanced survival for up to one year. Epicardial progenitors, marked by expression of the transcription factor Wt1 (Wilms Tumor Suppressor 1), were a major target of VEGF-A m*RNA activity. VEGF-A expanded and mobilized post-MI WT1+ epicardial progenitors. Remarkably, VEGF-A m*RNA altered the fate of these cells, enhancing their differentiation into endothelial cells and cardiomyocytes and reducing their differentiation into myofibroblasts. Our data suggest a novel therapeutic paradigm, in which brief activation of paracrine signaling pathways alters resident progenitor cell fate to achieve sustained therapeutic benefit. This cell-free therapeutic paradigm can be readily translated to large animal and clinical studies. In this proposal, we further investigate the regulation of adul epicardial cell behavior develop the therapeutic paradigm advanced by our preliminary data, through the following Specific Aims: (1) Determine the mechanism by which VEGF-A redirects EPDC fate. (2) Define the role of Wt1 in regulating adult epicardial progenitor activity in the normal and injured adult heart. (3) Identify additional factors with beneficial activity in myocardal infarction. By combining novel m*RNA technology with the Pu lab's established expertise in epicardial progenitors and their role in fetal and adult heart, this proposal will lead to mechanistic insights into myocardial regeneration, advance application of m*RNA technology to myocardial regeneration, and lead to new avenues for clinical translation.

描述（由申请人提供）：心力衰竭是全球发病率和死亡率的主要原因。当前的心力衰竭治疗在增强心肌修复或再生心脏肌肉方面无效。心肌梗塞后改善心肌修复将需要通过形成新的心肌细胞并支撑血管来增强边缘灌注和刺激心肌再生的区域的血管供应。 心外膜是覆盖心脏的两极化上皮，是胎儿心肌生长和冠状动脉血管生成的重要调节剂。心外膜和心肌进行精细的旁分泌信号传导，以调节彼此的发育。此外，心外膜细胞经历了间质转化（EMT）的上皮细胞，产生心外膜来源的间充质细胞（EPDC），这些细胞（EPDC）迁移到心脏中并区分成纤维细胞，血管平滑肌细胞，内皮细胞，潜在的心脏皮下部，以及潜在的心脏手势细胞。 在成人心脏中，心外膜是心肌损伤反应的重要调节剂，最近的研究表明，可以利用心外膜的发育特性用于治疗性再生。我们的初步数据表明，化学修饰的mRNA（M*RNA）在心脏中驱动短暂的高水平旁分泌因子表达。 VEGF-A M*RNA，在实验性心肌梗塞（MI）时进行一次，毛细血管密度增强，梗塞大小降低，射血分数的改善以及长达一年的生存率增强。以转录因子WT1（Wilms抑制剂1）的表达为特征的心外膜祖细胞是VEGF-A M*RNA活性的主要靶标。 VEGF-A扩展并动员了MI WT1+心外膜祖细胞。值得注意的是，VEGF-A M*RNA改变了这些细胞的命运，增强了它们分化为内皮细胞和心肌细胞，并将其分化减少为肌纤维细胞。我们的数据表明了一种新型的治疗范式，其中旁分泌信号通路的短暂激活改变了居民祖细胞命运，以实现持续的治疗益处。这种无细胞的治疗范例可以很容易地转化为大型动物和临床研究。 在该提案中，我们进一步研究了通过以下特定目的通过我们的初步数据提出的通用性心外膜细胞行为的调节：（1）确定VEGF-A重定向EPDC命运的机制。 （2）定义WT1在调节正常和受伤的成人心脏中调节成人心外膜祖细胞活性中的作用。 （3）确定在心肌梗塞中具有有益活动的其他因素。通过将新颖的M*RNA技术与PU实验室在心外膜祖细胞和胎儿和成人心脏中的作用相结合，该提议将导致对心肌再生的机械见解，将M*RNA技术提高应用于心肌再生，并导致临床翻译的新途径。