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: 10616178
• 负责人: Kari Lenhart
• 金额: $ 5.75万
• 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/10616178
• 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.

项目概要/摘要 这项研究的广泛目标是了解多个干细胞群的机制 由生态位控制以协调子细胞的生产。成体干细胞之间的协调是 对于维持组织稳态和防止肿瘤过度生长至关重要。许多结构，包括头发 卵泡、造血网络和发育中的卵巢需要严格控制干细胞增殖和 协调不同干细胞谱系的子细胞生产。在大多数情况下，分子 协调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 建立内源性微环境内干细胞纵向（20+小时）实时成像系统 我们已经开始揭示控制睾丸干细胞协调的机制。成体干细胞 睾丸的生殖干细胞 (GSC) 必须以精确的 2:1 比例产生子细胞，生殖细胞才能 有效分化为精子。我们的实时成像揭示了 GSC 中经过修改的胞质分裂程序： 仅在与两个子代正确关联后协调释放一个 GSC 子代的机制 体干细胞谱系。这种修改后的胞质分裂程序分两个阶段进行控制——暂停 受来自小生境的 Jak/STAT 信号传导调节，并触发来自细胞的胞质分裂的完成 成体干细胞。两个控制点都必须正确执行，否则干细胞胞质分裂失败，干细胞 肿瘤形成，生殖细胞无法分化。虽然我们已经确定了暂停和暂停的来源 触发，这些信号控制 GSC 胞质分裂的机制仍然未知。此外， 体细胞和种系沟通的程度，以确保产生适当比例的子细胞 很大程度上尚未开发。这项研究使用分子遗传学和扩展实时成像来询问特定的 生态位信号和成体干细胞结合调节 GSC 胞质分裂的机制，以确保 睾丸微环境中干细胞之间的协调。通过建立一种对两种干细胞进行实时成像的方法 群体中，我们现在还可以直接实时可视化干细胞协调并询问串扰 干细胞谱系之间的相互作用对于组织稳态至关重要。顺利完成拟议的 这项工作将为干细胞生态位相互作用以及这些相互作用如何被破坏提供重要的见解 在肿瘤发生过程中，为未来的工作奠定基础，旨在确定在肿瘤发生过程中发挥作用的类似机制 其他组织和物种。