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.

概括 成年斑马鱼具有非凡的心脏再生能力，并且疤痕最小。了解 潜在的细胞和分子机制将有助于解决成人的再生缺陷 哺乳动物的心脏。我们最近发现斑马鱼心外膜（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域（具有两个或多个拷贝 基因组）。在受伤后的许多哺乳动物器官中都观察到多倍体，并且最近已被证实 在组织修复机制中被调用。然而，多倍体的功能意义及其 组织修复的潜在机制仍然难以捉摸，这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，这些领导者心外膜 细胞引导尾部较小的分裂追随细胞群重新填充伤口。领导细胞 群体通过内复制建立和维持，并通过细胞凋亡消除 再生完成，表明作用是短暂的。领导细胞中升高的细胞张力驱动 内复制。领导细胞和追随细胞的这种协调行为促进了细胞的稳健再生 心外膜。此外，我们发现多倍体心外膜细胞是心脏旁分泌分泌的主要来源。 再生。我们提案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、报告基因检测和药物治疗，我们发现了一种新的信号传导 通路与 Yap 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、Yap 和调节新途径的信号级联 心外膜再生过程中的时空多倍化，2）定义驱动前导信号的前导信号 心外膜再生中的随动协调，3) 研究心外膜的功能意义 心脏再生中的多倍体。拟议的研究将定义引导细胞的新信号传导范式 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，例如 哺乳动物心肌细胞，以及肺损伤、急性肾损伤等病理过程， 和癌症。我们的研究结果将揭示有关细胞周期调节的概念创新 介导生理和病理多倍化以及强大的组织再生的决定。