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：
10680563
负责人：
Wuqiang Zhu
金额：
$ 66.8万
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/10680563
关键词：
Address Adhesives Adult Angiogenic Factor Antibodies Biocompatible Materials Birth Blood Vessels Blood flow Cardiac Cardiac Myocytes Cardiac Surgery procedures Case Study Cell Cycle Cell Survival Cells Chemicals Clinical Research Coculture Techniques Data Embryo Endothelial Cells Endothelium FDA approved Family suidae Fishes Functional disorder Future Ganglionectomy Generations Growth 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 Proliferating 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 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 neural network neurotrophic factor novel paracrine pharmacologic postnatal regeneration potential 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.

项目概要与低等脊椎动物的心肌细胞 (CM) 相比，成年哺乳动物 CM 具有非常有限的功能。由于细胞周期退出而具有再生潜力。有趣的是，新生小鼠保留了心脏再生能力能力，在出生后第 7 天就丧失了。我们最近表明，1 日龄的猪也可以恢复丧失的能力心肌对心肌梗塞（MI）的反应。这种再生是由增殖介导的先前存在的 CM，当 CM 永久退出细胞周期时不会发生这种情况。其背后的机制尤其是在大型哺乳动物中，损伤引起的再生反应尚未完全了解。然而，研究潜在机制可能会确定未来治疗干预的新目标。最近对鱼类和啮齿动物的研究强调了血管化和自主神经的至关重要性斑马鱼和新生小鼠心脏再生心肌的神经支配。除了它们的功能之外提供营养、运输代谢物并能够适应压力，目前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：可溶性因子，例如细胞因子，由血管内皮细胞和外周细胞分泌交感神经元显着刺激共培养的人诱导多能干细胞的细胞周期活性细胞衍生的 CM，表明非肌细胞-CM 相互作用在调节 CM 增殖中发挥着关键作用大型哺乳动物的心脏受伤后。在这个项目中，我们将利用已建立的高再生能力新生猪心脏模型的实验研究非肌细胞在损伤诱发的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后心脏再生中的血运重建。我们将检验早期的假设血运重建对于新生猪的心脏再生至关重要，并确定血管生成是否通过从内皮和/或平滑肌释放促肌原因子来促进心脏再生肌肉细胞和/或通过从头形成功能性血管来维持 CM 活力。目标 2 是描述自主神经支配在损伤后心脏再生中的作用。我们将测试假设神经支配对于新生猪损伤后心脏再生至关重要，并确定是否生物材料介导的心外膜递送血管生成和神经营养因子增强心脏再生心肌梗死后的新生猪。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gastroenteropancreatic Neuroendocrine Tumor Metastasis to the Heart: Evaluation of Imaging Manifestations.

胃肠胰神经内分泌肿瘤转移至心脏：影像学表现的评估。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Wang, Yuxiang;Ayoub, Chadi;Yang, Aaron F;Sonbol, Mohamad B;Butterfield, Richard;Halfdanarson, Thorvardur R;Arsanjani, Reza;Zhu, Wuqiang;Yang, Ming
通讯作者：
Yang, Ming

Gene Therapy for Cardiomyocyte Renewal: Cell Cycle, a Potential Therapeutic Target.

心肌细胞更新的基因治疗：细胞周期，潜在的治疗靶点。

DOI：
发表时间：
2023-03
期刊：
影响因子：
4
作者：
Son, Yura;Zhu, Wuqiang
通讯作者：
Zhu, Wuqiang

Peptide-Guided Nanoparticle Drug Delivery for Cardiomyocytes.

心肌细胞的肽引导纳米颗粒药物输送。

DOI：
发表时间：
2024-01-16
期刊：
影响因子：
4.2
作者：
Li, Dong;Taylor, Austin;Shi, Haiwang;Zhou, Fang;Li, Pengsheng;Joshi, Jyotsna;Zhu, Wuqiang;Wang, Shu
通讯作者：
Wang, Shu