Spatiotemporal regulation of polyploidy in zebrafish cardiac tissue regeneration

斑马鱼心脏组织再生中多倍体的时空调控

• 批准号: 10736051
• 负责人: Jingli Cao
• 金额: $ 72.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736051
• 关键词: Ablation; Activity Cycles; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Apoptosis; Behavior; Biological Assay; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Regulation; Cell Density; Cell Proliferation; Cell division; Cells; Chromosomes; Cicatrix; Cytokinesis; DNA; Defect; Development; Disease; Dominant-Negative Mutation; Epicardium; Fibroblasts; Genes; Genetic; Genome; Heart; Injury; Knowledge; Malignant Neoplasms; Mechanics; Mediating; Molecular; Myocardium; Natural regeneration; Normal tissue morphology; Nuclear; Organ; Paracrine Communication; Pathologic; Pathologic Processes; Pathway interactions; Pattern; Pericytes; Pharmacological Treatment; Physiological; Polyploid Cells; Polyploidy; Population; Process; Proliferating; Proteins; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; System; Testing; Tissues; Treatment Efficacy; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Vegf inhibition; Work; Zebrafish; age related; cardiac regeneration; cell behavior; cell motility; cell type; factor C; gain of function; human tissue; improved; innovation; loss of function; lung injury; mechanical signal; mechanotransduction; migration; novel; novel strategies; overexpression; paracrine; pharmacologic; progenitor; receptor; regeneration model; regenerative; repaired; single-cell RNA sequencing; spatiotemporal; tissue regeneration; tissue repair; tool; wound; wound healing

Summary Adult zebrafish have a remarkable capacity to regenerate the heart with minimal scarring. Understanding the underlying cellular and molecular mechanisms will help addressing the regenerative deficiency in the adult mammalian heart. We recently found that the zebrafish epicardium (the outermost layer of vertebrate hearts) regenerates after injury by the creation of a leader region of polyploid cells (having two or more copies of the genome). Polyploidy has been observed in many mammalian organs following injury and recently has been invoked in mechanisms of tissue repair. However, the functional significance of polyploidy, as well as its underlying mechanisms in tissue repair, remains elusive, representing a major knowledge gap in harnessing the advantages of polyploidy in tissue repair. We found that, through collective cell migration, these leader epicardial cells guide a trailing population of much smaller, dividing follower cells to repopulate the wound. The leader cell population is established and maintained by endoreplication and is eliminated through apoptosis upon completion of regeneration, indicating a transient role. The elevated cellular tension in the leader cells drives endoreplication. This coordinated behavior of leader and follower cells facilitates robust regeneration of the epicardium. Also, we found that the polyploid epicardial cells are a major source of paracrine secretion for heart regeneration. The overall objective of our proposal is to understand the mechanisms that regulate spatiotemporal cell behavior of the epicardium and how defects in this behavior impact heart regeneration. Through single-cell RNA sequencing, reporter assays, and pharmacological treatments, we have discovered a novel signaling pathway together with Yap signaling that participate in the spatiotemporal polyploidization in the epicardium. We will 1) characterize the signaling cascade that involves mechanical cues, Yap, and the new pathway in regulating spatiotemporal polyploidization during epicardial regeneration, 2) define the leader signals that drive leader- follower coordination in epicardial regeneration, and 3) investigate the functional significance of epicardial polyploidy in heart regeneration. The proposed research will define a new signaling paradigm in guiding cell cycle decisions for efficient heart regeneration. Moreover, polyploid cells are present in normal tissues such as the mammalian cardiomyocytes, as well as in pathological processes such as lung injury, acute kidney injury, and cancer. Results from our study will unearth conceptual innovations concerning the regulation of cell cycle decisions to mediate physiological and pathological polyploidization and robust tissue regeneration.

总结 成年斑马鱼具有非凡的心脏再生能力，且疤痕最小。了解 潜在的细胞和分子机制将有助于解决成人再生缺陷， 哺乳动物心脏我们最近发现，斑马鱼的心外膜（脊椎动物心脏的最外层） 通过产生多倍体细胞的前导区（具有两个或多个拷贝的 基因组）。在损伤后的许多哺乳动物器官中已经观察到多倍性，并且最近已经被证实为多倍性。 在组织修复机制中发挥作用。然而，多倍性的功能意义，以及其 组织修复的潜在机制仍然难以捉摸，代表了利用组织修复的主要知识差距。 多倍体在组织修复中的优势。我们发现，通过集体细胞迁移， 细胞引导一群更小的尾随的、分裂的跟随细胞来重新填充伤口。领导细胞 细胞群通过核内复制建立和维持， 完成再生，表明一个短暂的作用。领导细胞的细胞张力升高 核内复制领导者和跟随者细胞的这种协调行为促进了细胞的鲁棒再生。 心外膜同时，我们发现，多倍体心外膜细胞是心脏旁分泌的主要来源， 再生我们建议的总体目标是了解调节时空的机制 心外膜的细胞行为以及这种行为的缺陷如何影响心脏再生。通过单细胞 RNA测序、报告基因测定和药物治疗，我们发现了一种新的信号传导机制， 该信号通路与雅普信号一起参与心外膜的时空多倍化。我们 将1）表征涉及机械线索的信号级联，雅普，以及调节 在心外膜再生期间的时空多倍化，2）定义驱动leader的leader信号， 心外膜再生中的跟随者协调，以及3）研究心外膜再生的功能意义 心脏再生中的多倍性。这项研究将定义一种新的信号传导模式， 有效的心脏再生的周期决定。此外，多倍体细胞存在于正常组织中， 哺乳动物心肌细胞以及病理过程如肺损伤，急性肾损伤， 和癌症我们的研究结果将揭示有关细胞周期调控的概念创新 决定介导生理和病理多倍化和强大的组织再生。