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.

摘要 成年斑马鱼具有惊人的再生心脏的能力，几乎不会留下疤痕。了解 潜在的细胞和分子机制将有助于解决成人的再生缺陷 哺乳动物的心脏。我们最近发现斑马鱼的心外膜(脊椎动物心脏的最外层) 损伤后通过创建多倍体细胞的前导区(具有两个或更多拷贝的 基因组)。在损伤后的许多哺乳动物器官中观察到多倍体，最近被发现 在组织修复机制中被调用。然而，多倍体的功能意义以及它的 组织修复的潜在机制仍然难以捉摸，这代表着在利用 多倍体在组织修复中的优势。我们发现，通过集体细胞迁移，这些领头羊的心外膜 细胞引导一个小得多的、分裂的跟随细胞组成的拖尾细胞群重新填充伤口。先导细胞 种群的建立和维持是通过内复制，通过细胞凋亡来消除 再生完成，表明作用是暂时的。前导细胞中细胞张力的升高驱动 内复制术。前导细胞和从属细胞的这种协调行为促进了 心外膜。我们还发现，多倍体心外膜细胞是心脏旁分泌的主要来源。 再生。我们提案的总体目标是了解时空调控的机制 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。通过单电池 RNA测序、报告分析和药物治疗，我们发现了一种新的信号转导 途径和YAP信号一起参与心外膜的时空多倍化。我们 将1)描述涉及机械信号、YAP和调控中的新途径的信号级联 心外膜再生过程中的时空多倍化，2)定义了驱动导联的导联信号。 心外膜再生中的跟随者协调；3)探讨心外膜的功能意义 心脏再生中的多倍体。所提出的研究将定义一种新的引导细胞的信号范式 有效心脏再生的循环决策。此外，多倍体细胞存在于正常组织中，如 哺乳动物的心肌细胞，以及在肺损伤、急性肾损伤、 和癌症。我们的研究结果将发现关于细胞周期调控的概念创新 决定调节生理和病理的多倍化和强大的组织再生。