Cell competition and stem cell parasitism in a basal chordate

基底脊索动物的细胞竞争和干细胞寄生

• 批准号: 10017299
• 负责人: Anthony W De Tomaso
• 金额: $ 30.27万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017299
• 关键词: Adult; Affect; Animal Model; Area; Autocrine Communication; Biological Assay; Biology; Cells; Chordata; Clinical; Complex; Cues; Development; Developmental Process; Disease; Embryonic Development; Genotype; Germ Cells; Growth; Health; Heritability; Homeostasis; Homing; Human; Hydroxyeicosatetraenoic Acids; In Situ; In Vitro; Individual; Life; Lipids; Malignant Neoplasms; Modeling; Molecular; Natural regeneration; Nature; Normal Cell; Organ; Organism; Pathologic Processes; Pathway interactions; Phenotype; Play; Population; Process; Production; Property; Quality Control; Regenerative Medicine; Resolution; Resources; Rest; Role; Signal Transduction; Testing; Tissues; Transplantation; Tumor Suppressor Proteins; Urochordata; Variant; ascidian; base; cell motility; developmental disease; fitness; germline stem cells; in vivo; innovation; life history; loss of function; migration; neoplastic cell; novel; novel strategies; parasitism; polarized cell; progenitor; response; self-renewal; sensor; sphingosine 1-phosphate; stem cell biology; stem cell population; stem cells; trait; tumor initiation; tumor progression

ABSTRACT Cell competition is a process that compares the relative fitness of progenitor cells, resulting in `winners', which contribute further to development, and `losers', which are excluded, and is likely a universal quality control process that contributes to the fitness of an individual. Cell competition may also be involved in cancer, during which cells become `supercompetitors', subsequently outcompeting normal cells for resources and growth. Thus cell competition is a widespread phenomenon that has both developmental and disease relevance. However, the mechanisms underlying cell competition are not well understood. What is a sensor of fitness? Are there common regulatory mechanisms? How do the mechanisms underlying competition break down during disease? We are utilizing the unique biology of a model organism that will allow us to study these questions. Our model is the colonial tunicate, Botryllus schlosseri, which has germline stem cells (GSCs) that have genetically determined competitive phenotypes, with winner cells outcompeting loser cells. We can exploit the natural phenotypic variation present in our lab reared populations to characterize the mechanisms underlying cell competition. We can purify these cells to near homogeneity using FACS, transplant them, and quantify their contribution to gamete development. We have recently found that competitive differences may be in differences in migratory ability, specifically how cells responds to lipid signaling. In Aim 1, we will build upon these recent results, using both in vitro and in vivo assays developed in our lab to dissect the response of GSCs to lipid signaling. In Aim 2, we will take an unbiased approach, characterizing germ cell migration and development using different competitive genotypes developed in our lab, both in situ and during competition, following reciprocal transplantations, and utilize this natural phenotypic variation to pinpoint where competition may occur. Completion of the proposed aims will advance our understanding of the mechanisms which underlie competitive interactions between stem cells, which is becoming increasingly appreciated as a fundamental and conserved process in multicellular development, and may be important for instructing clinical regeneration using stem cells. When inappropriately activated, these competitive mechanisms may also be responsible for escape of normal growth control during cancer progression. Botryllus is a unique organism that allows novel approaches to study conserved molecular mechanisms of cell competition that underlie development, regenerative medicine, and cancer progression, areas of great importance for human health.

摘要 细胞竞争是比较祖细胞的相对适合度的过程，结果是 “赢家”和“输家”，前者对发展作出进一步贡献，后者被排除在外，很可能是 有助于个人健康的通用质量控制过程。细胞竞争可能 也与癌症有关，在癌症过程中，细胞成为“超级竞争者”，随后在竞争中胜出 为资源和生长提供正常细胞。因此，细胞竞争是一种普遍存在的现象， 发展和疾病的相关性。然而，细胞竞争背后的机制是 不是很清楚。什么是健康感应器？有没有共同的监管机制？做什么 在疾病期间，潜在的竞争机制会崩溃吗？ 我们正在利用一种模式生物的独特生物学，这将使我们能够研究这些问题。 我们的模型是殖民地被衣鱼Botryllus schlosseri，它拥有生殖系干细胞(GSCs)， 基因决定了竞争表型，胜利者细胞胜过失败者细胞。我们 可以利用我们实验室饲养的种群中存在的自然表型变异来表征 细胞竞争的潜在机制。我们可以用流式细胞仪将这些细胞纯化到接近均一的水平， 移植它们，并量化它们对配子发育的贡献。我们最近发现， 竞争性差异可能在于迁移能力的差异，特别是细胞对 脂质信号。在目标1中，我们将在这些最新结果的基础上，使用体外和体内测试。 我们实验室开发的用于分析GSCs对脂质信号的反应。在目标2中，我们将采取一种 不偏不倚的方法，用不同的竞争性来表征生殖细胞的迁移和发育 在我们的实验室中，无论是在原位还是在竞争过程中，都产生了如下的基因类型 并利用这种自然的表型变异来精确定位可能发生竞争的地方。 完成拟议的目标将促进我们对基础机制的理解 干细胞之间的竞争性相互作用，这越来越被认为是一种 在多细胞发育中的基本和保守的过程，可能对 使用干细胞指导临床再生。当不适当地激活时，这些竞争对手 在癌症进展过程中，机制也可能是逃避正常生长控制的原因。 Botryllus是一种独特的生物，它允许采用新的方法来研究保守的分子 发育、再生医学和癌症的细胞竞争机制 进步，对人类健康非常重要的领域。