Regulation of cellular plasticity and regeneration in Drosophila spermatogenesis

果蝇精子发生中细胞可塑性和再生的调节

• 批准号: 10431928
• 负责人: Erika L Matunis
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431928
• 关键词: Adopted; Adult; Automobile Driving; Biological; Biological Models; Biology; Cell Differentiation process; Cells; Collection; Drosophila genus; Fertility; Genetic; Germ Cells; Goals; Homeostasis; Image; Injury; Malignant Neoplasms; Molecular; Natural regeneration; Normal tissue morphology; Organ; Pathway interactions; Property; Signal Transduction; Spermatogenesis; Testis; Therapeutic; Tissues; Work; cell growth regulation; cell type; genome-wide; germline stem cells; interest; mature animal; programs; response; response to injury; single-cell RNA sequencing; stem cell biology; stem cells; tissue regeneration; tissue repair; tool

Abstract Many adult tissues replace cells lost due to normal wear and tear through the activity of stem cells, but can use entirely different strategies when injury occurs. The ability to understand and control regeneration, or the regrowth of lost tissues or organs in response to injury, is a long- standing goal in biology. Cells with the capacity to adopt the biological properties of other cell types under specific conditions, or cellular plasticity, are key contributors to regeneration. Stem cells and even differentiated cells can have surprising degrees of plasticity, allowing them to adopt new fates and rebuild damaged tissues. This happens in response to altered microenvironments that arise upon injury, but the mechanisms that regulate plasticity are poorly understood. We have developed the Drosophila testis as a model system to study the biology of stem cells and their microenvironments, or niches. Advantages include the relative simplicity of this tissue and an unparalleled collection of genetic tools to probe it functionally. Previously, we showed that damaging the Drosophila testis converts differentiating germ cells to revert to germline stem cells to repair the tissue. We recently found that quiescent somatic niche cells can transdifferentiate into new somatic stem cells upon damage. Here we combine live imaging, lineage tracing and single cell transcriptomic profiling to determine now niches sense damage and then activate program(s) to regenerate missing stem cells. We will also uncover the overall complexity of the genetic pathways enriched in the testis niche during normal tissue turnover, following up on candidate signals that relay information from stem cells to their niche. Our synergistic approach will enhance the understanding of the fundamental cellular and molecular mechanisms driving homeostasis and regeneration in the testis, which has important implications for understanding fertility, regeneration and cancer.

摘要 许多成年组织通过干细胞的活动来替换由于正常磨损而丢失的细胞 细胞，但可以使用完全不同的策略时，损伤发生。理解能力和 控制再生，或响应于损伤而再生失去的组织或器官，是一个长期的- 生物学中的固定目标具有吸收其他细胞生物学特性能力的细胞 在特定条件下的类型，或细胞的可塑性，是再生的关键因素。干 细胞甚至分化的细胞都有惊人的可塑性， 接受新的命运重建受损的组织这是对改变的 损伤后出现的微环境，但调节可塑性的机制很差 明白我们已经建立了果蝇睾丸作为研究生物学的模型系统 干细胞和它们的微环境，或者说小生境。优点包括相对简单 以及无与伦比的基因工具来探测它的功能。在此之前， 我们发现，损伤果蝇的睾丸可以将分化中的生殖细胞转化为 生殖干细胞来修复组织。我们最近发现静止的体细胞龛细胞 可以在受损后转分化为新的体干细胞。在这里我们将联合收割机 成像，谱系追踪和单细胞转录组学分析，以确定现在的小生境意义 损伤，然后激活程序来再生缺失的干细胞。我们还将揭开 在正常组织中，睾丸小生境中丰富的遗传途径的整体复杂性 周转，跟进从干细胞传递信息到其利基的候选信号。 我们的协同方法将增强对基本细胞和 驱动睾丸内稳态和再生的分子机制，这具有重要意义 对理解生育、再生和癌症的意义。