Extreme cell growth in support of stem cell proliferation and niche exit

极端的细胞生长支持干细胞增殖和利基退出

• 批准号: 10836751
• 负责人: Kacy Lynn Gordon
• 金额: $ 10.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836751
• 关键词: Adhesions; Adult; Animals; Area; Behavior; Biological Models; Cadherins; Caenorhabditis elegans; Candidate Disease Gene; Cell Fate Control; Cell Proliferation; Cell division; Cells; Cellular Structures; Complex; Cues; Development; Embryo; Genes; Germ Cells; Germ Lines; Goals; Gonadal structure; Growth; Health; Human; Larva; Life; Maintenance; Mediating; Microscopic; Modeling; Molecular; Organism; Pathway interactions; Proliferating; RNA Interference; Regulation; Research; Somatic Cell; Specific qualifier value; Stimulation of Cell Proliferation; Structure; System; Tissues; Undifferentiated; Work; candidate identification; cell growth; daughter cell; egg; follow-up; genetic analysis; genetic manipulation; germline stem cells; imaging study; in vivo imaging; insight; loss of function; neglect; next generation; pandemic disease; programs; self-renewal; sperm cell; stem cell division; stem cell fate; stem cell model; stem cell niche; stem cell population; stem cell proliferation; stem cells; success; transcriptome sequencing

K. Gordon, UNC R35 Abstract The specification and robust maintenance of the germ line stem cells and their differentiated descendants that form gametes are essential to the success of an organismal lineage. Stem cell niches are primary regulators of stem cell fate, which is characterized by continuous self-renewal with the capability of differentiation. Therefore the structure of stem cell niches—which often have extensive cellular contacts with their supported stem cell populations that must be broken by daughter cells that go on to differentiate—appear crucial for the regulation of the cell fate decision. Such contacts are shared in a variety of stem cell niches, but studies relating niche structure to function lag behind genetic analysis of stem cell regulation. Stem cell niches lie deep in tissues, making them difficult to observe, and stem cell divisions are stochastic. This proposal avoids these challenges by studying the germ line stem cell niche of C. elegans, an animal that is suited to multiplex in vivo imaging. The overall goal for the research program is to discover how undifferentiated germ stem cells receive cues from their micro-environment to stimulate proliferation and the cell fate switch to gamete differentiation, and how the dynamic cell structures supporting germ stem cells form. Conserved proliferation and cell growth pathways are relevant to human health. Pursuit of these questions will lead to insights that, like other findings made in this canonical stem cell niche model, may be broadly applicable to other stem cell systems. Overview of research and goals for the next five years: The Gordon Lab opened at UNC just before the pandemic began. It pursues key questions like: How do the stem cell niche and gonad sheath cells grow and internally partition themselves to interact appropriately with germ cells at different steps of the differentiation program? Both the niche cell and sheath undergo substantial growth and transformation during development. Both somatic cells will be genetically manipulated to determine if effects on germ cell proliferation are mediated by growth and partitioning of these regulatory cells. Cell-specific RNAi strains will be used to screen for genes resulting in diminished Sh1 growth and germ cell proliferation. What molecular mechanisms underlie oriented cell divisions at the niche boundary and asymmetrical cell fate acquisition? Spindle orientation has been studied in great detail in early C. elegans embryos, but it was not known that divisions in proliferating germ cells were oriented. Adhesion between the niche and germ cells was a neglected area of inquiry until recent findings implicated cadherin complexes—which orient spindles in the embryo—in the dramatic wrapping behavior of the niche around the stem cells. How does the stem cell niche mature from larvae to adults? RNA- seq of niche cells across the larva/adult transition will identify candidate genes that are correlated with the transition from a migratory niche during gonad growth to a stationary, mature adult niche. These and known genes will be investigated by tagging and loss of function analysis in live-imaging studies of the transition. Together this work will address arising and long-standing questions about a classical stem cell model system.

K. Gordon，WARR 35摘要 生殖系干细胞及其分化后代的特化和稳健维持， 配子的形成对生物谱系的成功是必不可少的。干细胞微环境是 干细胞命运，其特征在于具有分化能力的持续自我更新。因此 干细胞龛的结构--其通常与其支持的干细胞具有广泛的细胞接触 必须被继续分化的子细胞打破的细胞群似乎对调节至关重要 细胞命运的决定。这种接触在各种干细胞小生境中是共享的，但有关小生境的研究表明， 结构到功能落后于干细胞调控的遗传分析。干细胞壁龛位于组织深处， 这使得它们很难被观察到，而且干细胞分裂是随机的。这一建议避免了这些挑战 通过研究C. elegans，一种适合于体内多重成像的动物。 该研究项目的总体目标是发现未分化的生殖干细胞如何接受线索 从它们的微环境刺激增殖和细胞命运切换到配子分化，和 支持生殖干细胞的动态细胞结构如何形成。保守的增殖和细胞生长 路径与人类健康有关。对这些问题的追求将导致洞察力，就像其他发现一样， 在这个典型的干细胞生态位模型中，可以广泛地适用于其他干细胞系统。 研究概述和未来五年的目标：戈登实验室在2010年10月10日开幕之前， 大流行开始了。它追求的关键问题，如：干细胞龛和性腺鞘细胞如何生长， 在分化的不同阶段， 程序吗？在发育过程中，小生境细胞和鞘都经历了大量的生长和转化。 这两种体细胞将进行基因操作，以确定是否对生殖细胞增殖的影响是介导的 通过这些调节细胞的生长和分配。细胞特异性RNAi菌株将用于筛选基因 导致Sh 1生长和生殖细胞增殖减少。什么样的分子机制导致了 细胞分裂的生态位边界和不对称的细胞命运收购？主轴方向已被 在早期C.线虫胚胎，但不知道分裂增殖的胚芽， 细胞定向。直到最近，小生境和生殖细胞之间的粘附一直是一个被忽视的研究领域 研究结果表明，钙粘蛋白复合体--在胚胎中定向纺锤体--在戏剧性的包裹中， 干细胞周围的生态位的行为。干细胞龛是如何从幼虫成熟为成虫的？核糖核酸 在幼虫/成虫过渡期的小生境细胞的seq将识别与 从性腺生长期间的迁移生态位过渡到静止的成熟成年生态位。这些和已知的 基因将通过标记和功能丧失分析进行调查，在现场成像研究的过渡。 这项工作将共同解决有关经典干细胞模型系统的问题。

项目成果

The C. elegans gonadal sheath Sh1 cells extend asymmetrically over a differentiating germ cell population in the proliferative zone.

线虫性腺鞘 Sh1 细胞在增殖区的分化生殖细胞群中不对称地延伸。

• DOI: 10.7554/elife.75497
• 发表时间: 2022-09-12
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Li, Xin;Singh, Noor;Miller, Camille;Washington, India;Sosseh, Bintou;Gordon, Kacy Lynn
• 通讯作者: Gordon, Kacy Lynn