Mechanisms governing stem cell coordination by the niche

通过生态位控制干细胞协调的机制

• 批准号: 10029175
• 负责人: Kari Lenhart
• 金额: $ 31.24万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029175
• 关键词: Actins; Area; Basic Science; Biological Models; Cell Communication; Cell Count; Cell Lineage; Cell Proliferation; Cell Separation; Cell physiology; Cells; Cytokinesis; Daughter; Defect; Disease; Drosophila genus; Enhancers; Ensure; Environment; Excision; Failure; Feedback; Foundations; Future; Genetic; Germ Cells; Goals; Guanosine Triphosphate Phosphohydrolases; Hair follicle structure; Health; Hematopoietic; Homeostasis; Hour; Human; Image; Investigation; Knowledge; Length; Ligands; Link; Maintenance; Mediating; Methods; Modeling; Modification; Molecular; Molecular Genetics; Organ; Ovary; Pathway interactions; Play; Process; Production; Regulation; Rho-associated kinase; Role; Signal Transduction; Somatic Cell; Source; Structure; Supporting Cell; System; Testing; Testis; Time; Tissues; Tumor Stem Cells; Work; adult stem cell; cell type; cofilin; daughter cell; experimental study; fly; gene discovery; genetic analysis; genetic manipulation; germline stem cells; high resolution imaging; imaging approach; insight; neuronal cell body; notch protein; novel; prevent; programs; serial imaging; spatiotemporal; sperm cell; stem cell biology; stem cell division; stem cell niche; stem cell population; stem cell proliferation; stem cells; tissue degeneration; tumorigenesis

Project Summary / Abstract The broad objective of this study is to understand the mechanism by which multiple stem cell populations are controlled by the niche to coordinate daughter cell production. Coordination between adult stem cells is essential to maintain tissue homeostasis and prevent tumorous overgrowth. Many structures, including the hair follicle, hematopoietic network and developing ovary require tight control over stem cell proliferation and coordination of daughter cell production from distinct stem cell lineages. In most cases, the molecular mechanisms orchestrating this coordination are largely unknown. Leveraging the power of Drosophila genetics and establishing a system for longitudinal (20+ hours) live imaging of stem cells within an endogenous niche we have begun to reveal the mechanisms controlling stem cell coordination in the testis. Somatic stem cells and germline stem cells (GSCs) of the testis must generate daughters in a precise 2:1 ratio for germ cells to effectively differentiate into sperm. Our live imaging has revealed a modified cytokinesis program in GSCs as the mechanism to coordinate release of one GSC daughter only after it correctly associates with two daughters of the somatic stem cell lineage. This modified cytokinesis program is controlled at two stages—a pause regulated by Jak/STAT signaling from the niche and a trigger for completion of cytokinesis derived from the somatic stem cells. Both control points must be properly executed or stem cell cytokinesis fails, stem cell tumors form and germ cells fail to differentiate. While we have identified the source of both the pause and trigger, the mechanisms by which these signals control GSC cytokinesis remain unknown. In addition, the degree to which soma and germline communicate to ensure that proper ratios of daughter cells are produced is largely unexplored. This study uses molecular genetics and extended live imaging to interrogate the specific mechanisms by which niche signals and somatic stem cells combine to regulate GSC cytokinesis to ensure coordination between stem cells in the testis niche. By establishing a method for live imaging of both stem cell populations, we can now also directly visualize stem cell coordination in real time and interrogate the cross-talk between stem cell lineages that is essential for tissue homeostasis. Successful completion of the proposed work will provide significant insight into stem cell-niche interactions and how these may become disrupted during tumorigenesis, setting the foundation for future work aimed at identifying similar mechanisms at play in other tissues and species.

项目摘要 /摘要 这项研究的广泛目的是了解多个干细胞种群的机制 由利基控制以协调子细胞的产生。成年干细胞之间的协调是 维持组织体内稳态并防止肿瘤过度生长至关重要。许多结构，包括头发 植物，造血网络和发展卵巢需要严格控制干细胞增殖和 从不同的干细胞谱系中协调子细胞产生。在大多数情况下，分子 策划这种协调的机制在很大程度上是未知的。利用果蝇遗传学的力量 并建立一个内源性细胞中干细胞的纵向（20多个小时）的实时成像的系统 我们已经开始揭示控制睾丸中干细胞配位的机制。体干细胞 睾丸的种系干细胞（GSC）必须以生殖细胞的精度​​为2：1的女儿与 有效地分化为精子。我们的现场成像揭示了GSC中的一项修改的细胞因子程序 只有在将一个女儿与两个女儿相关联后，才能协调一个GSC女儿的机制 体细胞谱系的。该修改后的细胞因子程序在两个阶段进行控制 - 暂停 由利基市场受到JAK/Stat信号的调节，并触发了源自源自的细胞因子。 体干细胞。两个控制点必须正确执行或干细胞细胞因子失败，干细胞 肿瘤形成，生殖细胞无法区分。虽然我们已经确定了暂停和 触发，这些信号控制GSC细胞因子的机制仍然未知。另外， Soma和种系以确保产生适当比例的Soma和种系的程度 在很大程度上出乎意料。该研究使用分子遗传学和扩展的活成像来询问特定 利基信号和躯体干细胞结合起来调节GSC细胞因子以确保的机制 睾丸细胞中干细胞之间的协调。通过建立一种用于两个干细胞实时成像的方法 人群，我们现在还可以直接实时可视化干细胞配位并询问串扰 在组织稳态必不可少的干细胞谱系之间。成功完成拟议的 工作将提供对干细胞互动的重大见解，以及这些相互作用如何被破坏 在肿瘤发生期间，为未来的工作奠定基础，旨在确定相似的机制 其他组织和物种。