Understanding the molecular mechanism of cardiomyocyte dedifferentiation and proliferation during regeneration

了解再生过程中心肌细胞去分化和增殖的分子机制

• 批准号: 10541219
• 负责人: Michael WaiKok Tsang
• 金额: $ 54.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541219
• 关键词: Acceleration; Address; Adult; Amputation; Apical; Apoptosis; Automobile Driving; Cardiac; Cardiac Myocytes; Cause of Death; Cell Cycle; Cells; Centromere; Cessation of life; Cicatrix; Coronary Vessels; Cytokinesis; Endocardium; Endowment; Epicardium; Event; Excision; FOXM1 gene; Failure; G2/M Transition; Gene Expression; Genes; Genetic; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heterogeneity; In Situ; Infarction; Injury; M cell; Metabolic; Mitosis; Modeling; Molecular; Mutation; Myocardial; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Necrosis; Pathway interactions; Population; Process; Proliferating; Proteins; Recording of previous events; Regenerative response; Resected; Role; Societies; Testing; Tissues; Transcription Coactivator; Ventricular; Zebrafish; aurora B kinase; candidate identification; cardiac regeneration; cardiac repair; cdc Genes; cell injury; coronary vasculature; cyclin B3; forkhead protein; heart function; injured; loss of function; mutant; novel strategies; novel therapeutics; premature; prevent; repaired; response; response to injury; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transcriptomic profiling; ubiquitin-protein ligase

1 Heart disease is the leading cause of death and a significant health burden to society, in particular myocardial 2 infarctions are responsible for a large number of premature deaths world-wide. After a cardiac ischemic event, 3 damaged cells die via necrosis and apoptosis and is replaced by scar tissue. The presence of fibrotic scar tissue 4 diminishes cardiac function and overtime infarcted hearts undergo failure. Recent studies have shown that a 5 limited number of spared cardiomyocytes can dedifferentiate and proliferate in response to injury, but this 6 process fails to sufficiently replace lost cells. However, these studies offer new approaches to stimulate cardiac 7 repair. One clear obstacle is to understand the how mature mammalian cardiomyocytes are restricted from 8 proliferation in the adult hearts. Although the mammalian heart shows limited capacity in repair and regeneration, 9 the adult zebrafish heart is endowed with a robust regenerative response to a variety of injury models. The adult 10 zebrafish heart can efficiently replicate cardiomyocytes, and can stimulate endocardium and coronary vessel 11 regeneration such that damage or lost tissue is completely replaced within weeks. The major goal of this proposal 12 is to understand how the zebrafish heart, specifically cardiomyocytes are activated in response to ventricular 13 injury to dedifferentiate and proliferate. Findings from these studies will provide important factors that are critical 14 for driving completion of cardiomyocyte cell cycle after injury. In preliminary studies, we performed transcriptome 15 profiling (RNA-seq) on ventricular resected hearts and identified a number of genes that are highly expressed 16 following injury. Our studies reveal that one of these genes, the forkhead transcription factor, foxm1 is 17 upregulated in cardiomyocytes that are within the injury border zone. Studies with foxm1 mutant zebrafish 18 showed cardiomyocyte cell cycling was diminished and failure to resolve scar tissue upon ventricular resection. 19 Transcriptome profiling foxm1 mutant hearts show a marked decrease in expression of cell cycle genes involved 20 in G2/M transition suggesting that Foxm1 may be a critical driver of cardiomyocyte cytokinesis. In addition, we 21 have identified candidate foxm1 target genes implicated to be involved in cardiomyocyte differentiation and 22 mitosis. We therefore propose to characterize the molecular control of cardiomyocyte dedifferentiation and 23 proliferation through extensive study of foxm1 and downstream target genes. The findings from these studies 24 will identify new molecular pathways and factors to that have the potential to stimulate repair and regeneration 25 after myocardial infarction to address a societal health burden.

1心脏病是导致死亡的主要原因，也是社会的重大健康负担，尤其是心脏病 2脑梗塞是全球范围内大量过早死亡的原因。在心脏缺血事件之后， 3受损细胞通过坏死和凋亡而死亡，并被瘢痕组织所取代。纤维性瘢痕组织的存在 4会降低心功能，随着时间的推移，梗死的心脏会衰竭。最近的研究表明， 5有限数量的备用心肌细胞可以在损伤后去分化和增殖，但这 6过程不能充分替换丢失的信元。然而，这些研究提供了新的方法来刺激心脏 7.维修。一个明显的障碍是理解成熟的哺乳动物心肌细胞是如何受到限制的 8成人心脏的增殖。尽管哺乳动物心脏的修复和再生能力有限， 成年斑马鱼的心脏对各种损伤模型具有强大的再生反应。成年人 10只斑马鱼心脏可以高效复制心肌细胞，并能刺激心内膜和冠状动脉 11再生，使受损或丢失的组织在几周内完全修复。这项提案的主要目标是 12是为了了解斑马鱼的心脏，特别是心肌细胞是如何被激活的 13损伤为去分化和增殖。这些研究的结果将提供至关重要的重要因素 14用于推动损伤后心肌细胞周期的完成。在初步研究中，我们进行了转录组 15对切除的心脏的RNA-seq分析，并确定了一些高表达的基因。 伤后16例。我们的研究表明，其中一个基因，叉头转录因子FOXM1是 17在损伤交界区的心肌细胞中表达上调。FOXM1突变体斑马鱼的研究 18例显示心肌细胞周期受抑，脑室切除后瘢痕组织不能溶解。 19个转录组分析FOXM1突变心脏显示相关细胞周期基因的表达显著减少 20处于G2/M期，提示FOXM1可能是心肌细胞胞质分裂的关键驱动因子。此外，我们 21个已确定FOXM1候选靶基因参与心肌细胞分化和 22有丝分裂。因此，我们建议表征心肌细胞去分化的分子控制和 23通过对FOXM1及其下游靶基因的广泛研究实现增殖。这些研究的发现 24将确定有可能刺激修复和再生的新的分子途径和因子 25心肌梗死后应对社会健康负担。