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.

项目概要/摘要 细胞更新对于上皮组织的形式和功能至关重要。细胞更新速度减慢 衰老，在损伤和修复过程中会加速，在癌变过程中会受到提早刺激；但是 在活体组织中引导它的机制尚不清楚。我们最近发现，消除不合格的 细胞从上皮细胞中挤出，刺激附近干细胞的增殖，以取代丢失的细胞并维持 组织中的总细胞数。这一有趣的发现表明挤压提供了细胞损失之间的关键联系 和增殖，从而控制细胞更新率。因此，识别机制 潜在的挤压可能为内生过程提供新的见解，可用于促进 细胞替换或防止不必要的新细胞添加。我们的长期目标是定义蜂窝 以及上皮组织细胞更新率的分子机制。使用正在开发的 斑马鱼研究活体上皮组织中的细胞挤出，我们发现注定要挤出的细胞改变了它们的 以脉动肌动球蛋白收缩形式表现的机械特性，由肌动球蛋白的富集控制 生物活性脂质 1-磷酸鞘氨醇 (S1P)。我们还询问了细胞损失诱导的信号事件 和细胞反应，包括炎症细胞募集和表皮细胞增殖，驱动 周转。我们发现表皮生长因子受体配体表观基因的表达显着上调 (EPGN) 在诱导细胞挤压后，表明 EPGN 的短暂增加可能有助于维持上皮细胞 细胞损失期间的形式和功能。与这个想法一致，我们发现用重组人进行治疗 EPGN (hrEPGN) 在受到损伤刺激后抑制上皮细胞挤出，从而减少 代偿性干细胞增殖。这些数据得出这样的假设：EPGN 调节挤压来决定 上皮组织中的细胞更新率。研究细胞更新和测试的一项艰巨挑战 在活的有机体中的这一假设涉及可视化和扰乱挤压之间复杂的相互作用 细胞、替代丢失细胞的周围干细胞和免疫细胞来感知和响应干扰 诚信。因此，我们创建了单独操纵不同细胞和分子成分的工具 或结合在发育中的斑马鱼的活上皮组织中，并分析其周转的变化 先天免疫系统的存在。我们在未来五年的工作中将采用这种新方法，并将 重点关注我们正在进行的研究中出现的三个重要领域，并解决我们知识中的关键差距 细胞更新。首先，我们将确定调节物理力局部变化的机制 需要通过挤压去除有缺陷的细胞。其次，我们将确定细胞损失如何促进 周围干细胞表观遗传和转录状态的变化，以刺激增殖和 替换丢失的细胞。第三，我们将确定先天免疫系统在促进细胞更新中的作用 和维持上皮组织稳态。