Regulation of Overall Cell Numbers During Epithelial Tissue Homeostasis and Pathogenesis

上皮组织稳态和发病机制中总细胞数量的调节

• 批准号: 10621985
• 负责人: George Thomas Eisenhoffer
• 金额: $ 42.12万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621985
• 关键词: Acceleration; Actomyosin; Address; Aging; Area; Cell Count; Cell Proliferation; Cells; Complex; Data; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial Cells; Epithelium; Event; Genetic Transcription; Goals; Homeostasis; Human; Immune; Individual; Inflammatory; Innate Immune System; Knowledge; Ligands; Link; Lipids; Maintenance; Molecular; Organism; Pathogenesis; Process; Proliferating; Recombinants; Regulation; Role; Signal Induction; Stimulus; Testing; Tissues; Visualization; Work; Zebrafish; carcinogenesis; epigen; injury and repair; insight; mechanical properties; novel strategies; prevent; recruit; response; sphingosine 1-phosphate; stem cell proliferation; stem cells; tool

PROJECT SUMMARY/ABSTRACT Cellular turnover is essential for the form and function of epithelial tissues. The rate of cell turnover slows during aging, can be accelerated during injury and repair, and is precociously stimulated during carcinogenesis; but the mechanisms guiding it in living tissues is not well understood. We recently discovered that elimination of unfit cells by extrusion from epithelia stimulates proliferation of nearby stem cells to replace the lost cells and maintain overall cell numbers in the tissue. This intriguing finding suggests extrusion provides a key link between cell loss and proliferation, and thereby controls the rate of cell turnover. Thus, identification of the mechanisms that underlie extrusion may provide new insights into endogenous processes that can be leveraged to promote cellular replacement or prevent the unwanted addition of new cells. Our long-term goal is to define the cellular and molecular mechanisms underlying the rate of cellular turnover in epithelial tissues. Using the developing zebrafish to study cell extrusion in a living epithelial tissue, we have found that cells fated to extrude alter their mechanical properties in the form of pulsatile actomyosin contractions that are controlled by enrichment of the bioactive lipid sphingosine-1-phosphate (S1P). We have also interrogated the cell loss-induced signaling events and cellular responses, including inflammatory cell recruitment and epidermal cell proliferation, that drive turnover. We identified a significant upregulated expression of the epidermal growth factor receptor ligand epigen (EPGN) upon induced cell extrusion, suggesting that transient increases in EPGN may aid in sustaining epithelial form and function during cell loss. Consistent with this idea, we found that treatment with recombinant human EPGN (hrEPGN) suppressed epithelial cell extrusion after receiving damage stimuli, which in turn reduced the compensatory stem cell proliferation. These data led to the hypothesis that EPGN regulates extrusion to dictate the rate of cellular turnover in epithelial tissues. One formidable challenge to studying cellular turnover and testing this hypothesis in a living organism involves visualizing and perturbing the complex interplay between extruding cells, the surrounding stem cells that replace the lost cells and immune cells to sense and respond to disruptions in integrity. Therefore, we created tools to manipulate different cellular and molecular components individually or in combination in living epithelial tissues of developing zebrafish and analyze changes to turnover in the presence of an innate immune system. Our work over the next five years we utilize this new approach and will focus on three essential areas that emerged from our ongoing studies and address key gaps in our knowledge of cellular turnover. First, we will determine the mechanisms regulating the localized changes in physical forces that are required to remove defective cells by extrusion. Second, we will determine how cell loss promotes changes in the epigenetic and transcriptional states in surrounding stem cells to stimulate proliferation and replace the lost cells. Third, we will determine the role of the innate immune system in promoting cell turnover and maintenance of epithelial tissue homeostasis.

项目摘要/摘要 细胞更新对于上皮组织的形式和功能至关重要。细胞周转率在 衰老，可以在受伤和修复过程中加速，并在癌变期间先刺激；但是 引导在活组织中引导它的机制尚不清楚。我们最近发现消除不合适的 细胞通过上皮挤出会刺激附近干细胞的增殖，以取代丢失的细胞并维持 组织中的整体细胞数。这个有趣的发现表明挤出提供了细胞损失之间的关键联系 和增殖，从而控制细胞更新的速度。因此，识别机制 挤压基础可能会为内源性过程提供新的见解，以促进 细胞置换或防止不需要添加新细胞。我们的长期目标是定义细胞 以及上皮组织中细胞更新率的基础的分子机制。使用开发 斑马鱼研究活着的上皮组织中的细胞挤出 机械性能以脉动肌球蛋白收缩的形式由富集控制 生物活性脂质鞘氨醇1-磷酸（S1P）。我们还询问了细胞损耗引起的信号传导事件 和细胞反应，包括炎性细胞募集和表皮细胞增殖，驱动 周转。我们确定了表皮生长因子受体配体表皮的显着上调表达 （EPGN）在诱导细胞挤出后，表明EPGN的瞬时增加可能有助于维持上皮 细胞丢失期间的形式和功能。与这个想法一致，我们发现重组人的治疗 EPGN（HREPGN）收到损伤刺激后抑制上皮细胞挤出，进而降低了 补偿性干细胞增殖。这些数据导致了以下假设：EPGN调节挤压以决定 上皮组织中细胞周转率。研究细胞周转和测试的一个巨大挑战 活生物体中的这一假设涉及可视化和扰动挤出之间的复杂相互作用 细胞，替代丢失细胞和免疫细胞的周围干细胞感知并响应破坏 诚信。因此，我们创建的工具可以单独操纵不同的细胞和分子成分 或结合生存斑马鱼的生存上皮组织，并分析了转换的变化 存在先天免疫系统。在接下来的五年中，我们的工作利用了这种新方法，并将 专注于我们正在进行的研究中出现的三个基本领域，并解决我们知识的关键差距 细胞更新。首先，我们将确定调节物理力局部变化的机制 通过挤出去除有缺陷的细胞所需的。其次，我们将确定细胞损失如何促进 周围干细胞中表观遗传和转录状态的变化，以刺激增殖和 更换丢失的单元。第三，我们将确定先天免疫系统在促进细胞更新中的作用 并维持上皮组织稳态。