Mechanisms of alternative fate decision in mammalian spermatogonial stem cells

哺乳动物精原干细胞的选择性命运决定机制

• 批准号: 8512509
• 负责人: Zhuoru Wu
• 金额: $ 18.81万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512509
• 关键词: Adopted; Adult; Aging; Cell Line; Cell physiology; Cells; Commit; Cues; Data; Decision Making; Disease; Environment; Equilibrium; Fertility; Gene Expression; Genes; Genetic Screening; Germ Lines; Goals; Gonadal structure; Homeostasis; Human; In Vitro; Individual; Infertility; Intrinsic factor; Lead; Malignant Neoplasms; Mammals; Modeling; Molecular; Molecular Profiling; Mus; Nature; Organ; Outcome; Phenotype; Physiological; Population; Probability; Published Comment; Publishing; Regulation; Rodent; Role; Series; Signal Transduction; Spermatogenesis; Stem Cell Research; Stem cells; Stimulus; System; Tissue Differentiation; Tissues; Tretinoin; base; birth control; cell fate specification; cell type; gene therapy; in vivo; insight; novel; novel therapeutic intervention; overexpression; public health relevance; self-renewal; stem cell biology; stem cell fate; transcription factor

DESCRIPTION (provided by applicant): In most mammalian tissues, homeostasis is maintained by tissue stem cells that function through continued self-renewal and differentiation. Despite the importance of this cell fate decision to tissue homeostasis, the general rules by which stem cell progeny commit to the paths of self- renewal or differentiation are largely unknown. Most current paradigms presume that environmental cues determine the fate of individual stem cell progeny. Unexpectedly, our preliminary data and published studies show that rodent spermatogonial stem cell (SSC) progeny autonomously elicit self-renewal and differentiation in a stochastic manner with constant probability, and that this balance may be regulated by extrinsic cues. These findings point to new mechanisms guiding mammalian SSC self-renewal and differentiation, which will likely prove relevant to other stem cell types. Here w propose to investigate the physiological regulation and the molecular components governing mouse SSC stochastic fate choice. Specifically, we will examine the role of specific internal and external factors that can influence fate choice of SSC progeny and identify novel SSC intrinsic factors that promote self-renewal through a genetic screen. Insights from this study may provide the basis for new therapeutic interventions that restore fertility and optimize birth control.

描述（由申请人提供）：在大多数哺乳动物组织中，体内平衡由组织干细胞维持，组织干细胞通过持续的自我更新和分化发挥作用。尽管这种细胞命运决定对组织稳态的重要性，但干细胞后代致力于自我更新或分化的途径的一般规则在很大程度上是未知的。大多数目前的范例假设，环境因素决定个体干细胞后代的命运。出乎意料的是，我们的初步数据和已发表的研究表明，啮齿类动物精原干细胞（SSC）的后代自主地引发自我更新和分化的随机方式与恒定的概率，这种平衡可能受到外部线索。这些发现指出了指导哺乳动物SSC自我更新和分化的新机制，这可能与其他干细胞类型有关。本文旨在探讨小鼠SSC随机命运选择的生理调控机制及其分子组成。具体来说，我们将研究特定的内部和外部因素的作用，可以影响命运选择的SSC后代，并确定新的SSC的内在因素，促进自我更新，通过遗传筛选。这项研究的见解可能为恢复生育能力和优化生育控制的新治疗干预提供基础。