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