Regulation of Cell Turnover During Epithelial Tissue Homeostasis

上皮组织稳态期间细胞更新的调节

• 批准号: 9888212
• 负责人: George Thomas Eisenhoffer
• 金额: $ 40.47万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888212
• 关键词: Active Biological Transport; Adult; Aging; Apoptosis; Apoptotic; Area; Asthma; Basal Cell; Biological Models; Birth; Carcinoma; Cell Count; Cell Death; Cell Proliferation; Cell division; Cells; Cessation of life; Colitis; Dangerousness; Data; Development; Disease; Drosophila genus; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelial Cells; Epithelium; Event; Excision; Failure; Future; Genetic; Goals; Homeostasis; Human; Human Pathology; Hyperplasia; Image; Impairment; Individual; Larva; Lead; Life; Link; Maintenance; Mediating; Molecular; Monitor; Natural regeneration; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phagocytes; Physiological; Population; Population Dynamics; Process; Production; Proliferating; Regulation; Signal Transduction; Sum; System; Testing; Time; Tissues; Visualization; WNT Signaling Pathway; Work; Zebrafish; base; carcinogenesis; cell behavior; cell growth regulation; epithelial stem cell; gene function; genetic regulatory protein; human disease; improved; in vivo; insight; intestinal epithelium; novel; optogenetics; overexpression; prevent; response; restoration; stem cell population; stem cell proliferation; stem cells; tissue regeneration; tool

PROJECT SUMMARY ABSTRACT Cells within epithelial tissues are continually being eliminated by apoptosis and replaced by cell proliferation, however the mechanisms that coordinate cell removal with cell division to retain constant cell numbers remain unknown. Failure to coordinate the birth and death of cells can lead to dysregulation of population numbers and compromised barrier function, or conversely, tissue hyperplasia and carcinoma formation. Thus, a thorough understanding of the genetic underpinnings guiding cellular turnover in epithelial tissues will provide insight into molecular pathways that can be leveraged against diverse human pathologies by enhancing the removal and replacement of defective cells. The goal of this proposal is to define the cell and molecular mechanisms that regulate cell turnover in epithelial tissues to maintain appropriate overall population numbers. My recent results suggest that clearance of excess or defective cells was a major influence in whether neighboring cells would divide, extrude or die. Importantly, this work also suggested that alterations in the ability to rapidly clear apoptotic cells from the epithelial tissues may lead to several epithelial pathologies, including decreased barrier function in the intestinal epithelium or the accumulation of dangerous cells to promote carcinoma formation. Yet, a model system has been lacking to study how changes in apoptotic cell clearance could impact cell turnover and tissue maintenance in living epithelia. To investigate cell turnover in a living epithelial tissue, we have developed a toolset to perturb gene function and perform live imaging of division and death in the epithelia of the developing zebrafish, providing unparalleled access to analyze cell turnover in real time. Using the developing zebrafish to study cellular turnover in an epithelial bilayer, we have uncovered that induction of damage in a subset of basal epithelial cells promotes live cell neighbors to act as phagocytes that rapidly clear the apoptotic cellular debris. The basal stem cells then undergo division to compensate for the cell loss and maintain tissue integrity and function. Our preliminary data suggests that inhibition of either cell death or WNT signaling eliminates the apoptosis-induced division and results in failed regeneration. Further, genetic overexpression of WNT signaling in the context of a damage response led to an increase in overall cell numbers. In the following proposal, we will test the hypothesis that clearance of WNT-containing apoptotic cells by neighboring stem cells directly influences their proliferation to drive cell turnover in epithelia. In Aim 1, we will determine how removal of dying cells stimulates stem cell-mediated replacement. In Aim 2, we will define the molecular mechanisms guiding apoptosis-induced proliferation to maintain overall cell numbers. In Aim 3, we will determine if apoptotic bodies and microparticles can promote stem cell proliferation. Together, these studies will help reveal the cell and molecular events regulating epithelial tissue homeostasis and how alterations lead to human pathogenic conditions.

项目概要摘要 上皮组织内的细胞不断地被细胞凋亡所消除，并被细胞增殖所取代， 然而，协调细胞去除和细胞分裂以保持恒定细胞数量的机制仍然存在 未知。未能协调细胞的出生和死亡可能会导致细胞数量失调 屏障功能受损，或者相反，组织增生和癌形成。于是，彻底的 了解指导上皮组织细胞更新的遗传基础将有助于深入了解 分子途径可以通过增强去除和作用来对抗不同的人类病理学 更换有缺陷的电池。该提案的目标是定义细胞和分子机制 调节上皮组织中的细胞更新以维持适当的总体数量。我的 最近的结果表明，清除多余或有缺陷的细胞是相邻细胞是否存在的主要影响因素。 细胞会分裂、挤出或死亡。重要的是，这项工作还表明，快速反应能力的改变 上皮组织中清除的凋亡细胞可能导致多种上皮病变，包括细胞凋亡减少 肠上皮的屏障功能或危险细胞的积累促进癌症 形成。然而，一直缺乏模型系统来研究凋亡细胞清除的变化如何影响 活上皮细胞的细胞更新和组织维护。为了研究活上皮组织中的细胞更新， 我们开发了一套工具来扰乱基因功能并对分裂和死亡进行实时成像 发育中的斑马鱼的上皮细胞，为实时分析细胞更新提供了无与伦比的途径。使用 正在发育的斑马鱼研究上皮双层中的细胞更新，我们发现诱导 基底上皮细胞亚群的损伤促进邻近的活细胞充当吞噬细胞，快速清除 凋亡的细胞碎片。然后基底干细胞进行分裂以补偿细胞损失并 维持组织完整性和功能。我们的初步数据表明，抑制细胞死亡或 WNT 信号传导消除了细胞凋亡诱导的分裂并导致再生失败。此外，遗传 损伤反应中 WNT 信号的过度表达导致细胞总数增加。 在下面的提案中，我们将检验以下假设：清除含有 WNT 的凋亡细胞 邻近干细胞的作用直接影响其增殖，从而驱动上皮细胞的细胞更新。瞄准 1，我们将确定死亡细胞的去除如何刺激干细胞介导的替代。在目标 2 中，我们将 定义指导细胞凋亡诱导增殖以维持细胞总数的分子机制。在 目标3，我们将确定凋亡小体和微粒是否可以促进干细胞增殖。一起， 这些研究将有助于揭示调节上皮组织稳态的细胞和分子事件以及如何 改变导致人类致病。