Cardiomyocyte Non-autonomous Factors and Cardiac Regeneration in Large Mammals

大型哺乳动物心肌细胞非自主因素与心脏再生

基本信息

批准号：
10515862
负责人：
Wuqiang Zhu
金额：
$ 68.45万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-09 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515862
关键词：
Address Adhesives Adult Angiogenic Factor Antibodies Biocompatible Materials Birth Blood Vessels Blood flow Cardiac Cardiac Myocytes Case Study Cell Cycle Cell Survival Cells Chemicals Clinical Research Data Embryo Endothelial Cells Endothelium FDA approved Family suidae Fishes Functional disorder Future Ganglionectomy Heart Heart Injuries Human Hydrogels Injury Intervention Link Maintenance Mammals Maps Mediating Modeling Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Neonatal Nerve Growth Factors Neuregulin 1 Neurons Newborn Infant Nutrient Operative Surgical Procedures Patients Peripheral Pharmacology Proteomics Publications Radionuclide Imaging Recombinants Regenerative capacity Regenerative response Reporting Research Rodent Role Signal Pathway Smooth Muscle Myocytes Stress Testing Therapeutic Therapeutic Intervention Vagotomy Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascularization Ventricular Vertebrates Zebrafish angiogenesis base bevacizumab cardiac regeneration cardiogenesis congenital heart disorder cytokine enhancing factor experimental study fetal heart innervation induced pluripotent stem cell derived cardiomyocytes ischemic injury mouse model nanoparticle delivery neonatal mice nerve supply neural network neurotrophic factor novel paracrine postnatal regeneration potential relating to nervous system response single-cell RNA sequencing ultrasound

项目摘要

Project Summary In contrast to the cardiomyocytes (CMs) from lower vertebrates, adult mammalian CMs possess very limited regenerative potential as a result of cell cycle exit. Interestingly, neonatal mice retain cardiac regenerative capacity, which is lost by postnatal day 7. We have recently shown that 1-day-old pigs can also regenerate lost myocardium in response to myocardial infarction (MI). This regeneration is mediated by the proliferation of preexisting CMs, which does not occur when CMs permanently exit the cell cycle. Mechanisms underlying the injury-mounted regenerative response especially in large mammals are not fully understood. However, investigating underlying mechanisms is likely to identify novel targets for future therapeutic interventions. Recent studies in fish and rodents emphasized the critical importance of vascularization and autonomic innervation of the regenerating myocardium in zebrafish and neonatal mouse hearts. Besides their function to provide nutrients, transport metabolites and enable adaptation to stress, it is unknown whether vascular and neuronal cells, via paracrine interactions, also promote CM proliferation. Intriguingly, our preliminary data support the idea that soluble factors, e.g., cytokines, secreted from vascular endothelial cells and peripheral sympathetic neurons significantly stimulate cell cycle activity of co-cultured human induced pluripotent stem cells-derived CMs, suggesting a critical role of nonmyocyte-CM interactions in modulating CM proliferation in hearts of larger mammals post injury. In this project, we will exploit the established high regenerative capacity of the neonatal pig heart model to experimentally address the role of nonmyocytes in injury-induced cardiac regeneration in large mammals. Two specific aims are proposed. Aim 1 is to define the role of early revascularization in injury-mounted cardiac regeneration. We will test the hypothesis that early revascularization is essential for cardiac regeneration in neonatal pigs, and determine whether angiogenesis promotes cardiac regeneration through the release of pro-myogenic factors from endothelial and/or smooth muscle cells and/or via de novo formation of functional vessels for maintenance of CM viability. Aim 2 is to delineate the role of autonomic innervation in injury-mounted cardiac regeneration. We will test the hypothesis that innervation is essential for post injury cardiac regeneration in neonatal pigs, and determine if biomaterial-mediated epicardial delivery of angiogenic and neurotrophic factors enhances cardiac regeneration in neonatal pigs post MI.

项目摘要与下脊椎动物的心肌细胞（CMS）相反，成年哺乳动物CM非常有限细胞周期出口导致再生潜力。有趣的是，新生小鼠保留心脏再生容量，在产后第7天就丢失了。我们最近表明1天大的猪也可能会再生响应心肌梗塞（MI）的心肌。这种再生是由先前存在的CM，当CMS永久退出细胞周期时不会发生。基础的机制尤其是在大型哺乳动物中造成损伤的再生反应。然而，研究基本机制可能会确定未来治疗干预措施的新目标。鱼类和啮齿动物的最新研究强调了血管形成和自主神经的重要性斑马鱼和新生小鼠心脏中再生心肌的神经。除了它们的功能提供营养素，运输代谢物并使适应压力适应，尚不清楚血管和神经元细胞通过旁分泌相互作用也促进CM增殖。有趣的是，我们的初步数据支持以下观点，例如可溶性因子，例如细胞因子，从血管内皮细胞和周围分泌交感神经元显着刺激共培养的人类诱导多能茎的细胞周期活性细胞来源的CM，表明非甲状腺细胞相互作用在调节CM增殖中的关键作用受伤后大型哺乳动物的心脏。在这个项目中，我们将利用既定的高再生能力新生儿猪心脏模型的实验性解决非甲虫细胞在损伤诱导心脏中的作用大型哺乳动物的再生。提出了两个具体目标。目标1是定义早期的作用损伤的心脏再生中的血运重建。我们将测试早期的假设血运重建对于新生儿猪的心脏再生至关重要，并确定是否是血管生成通过从内皮和/或光滑的促肌原生成因子释放来促进心脏再生肌肉细胞和/或通过从头形成功能血管，以维持CM生存能力。目标2是描述自主神经在损伤安装心脏再生中的作用。我们将测试假设神经对于新生儿猪的损伤后心脏再生至关重要，并确定是否是否生物材料介导的心外膜输送的血管生成和神经营养因子增强了心脏再生在新生儿猪中。