Aging and Ovarian Stem Cell Niche Dysfunction

衰老与卵巢干细胞生态位功能障碍

• 批准号: 8738557
• 负责人: Ning Wang
• 金额: $ 24.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738557
• 关键词: Ablation; Accounting; Adult; Affect; Age; Aging; Aging-Related Process; Area; Atrophic; Award; Biology; Biology of Aging; Birth; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Clinical Medicine; Commit; Data; Deterioration; Disease; Elderly; Event; Failure; Female; Fertility; Fibroblast Growth Factor; Foundations; Functional disorder; Future; Goals; Health; Hematopoietic; In Vitro; Lead; Life Expectancy; Longevity; Maintenance; Mammals; Meiosis; Menopause; Mentors; Mitotic Activity; Modeling; Mus; Natural regeneration; Neuraxis; Neuroglia; Oocytes; Organ; Ovarian; Ovary; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Phase; Phenotype; Physiological; Play; Premature Ovarian Failure; Primordial Follicle; Process; Proliferating; Property; Regulation; Reporter; Reporting; Role; Solid; Somatic Cell; Stem cells; Technology; Telomerase; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; Undifferentiated; Vascular Endothelial Cell; Woman; adult stem cell; advanced maternal age; age related; aged; base; cancer therapy; daughter cell; embryonic stem cell; emerging adult; exhaustion; fibroblast growth factor 9; functional decline; improved; in vivo; induced pluripotent stem cell; insight; male; mouse model; neurotrophic factor; new therapeutic target; novel; offspring; ovarian failure; public health relevance; regenerative; reproductive; stem cell biology; stem cell differentiation; stem cell niche; suicide gene; therapeutic target; transgenic suicide gene

Project Summary One of the most exciting areas of stem cell biology relates to the possibility that stem cell dysfunction plays central role in aging-related deterioration of organ function. Recent studies suggest that oogonial (oocyte- producing) stem cells (OSCs) exist in the adult mammalian ovary. Existence of OSCs raises the possibility that ovarian aging, marked by loss and exhaustion of oocyte-containing follicles, may similarly involve a progressive loss of stem cell function. Thus, it is now important to establish the physiological roles of OSCs in ovarian function and aging. My long-term goal is to determine how the aging process negatively affects OSC function, and thus use OSCs as a model to provide insight into stem cell-based mechanisms for organismal aging. Specifically, I propose to use novel suicide gene transgenic (sg-Tg) mouse models we have developed over the past three years to study this. These mouse models are unique in that differentiating OSC daughter cells can be selectively targeted and ablated using suicide gene technology. In our preliminary data, we show that selective disruption of these OSC differentiation pathways results in a genetically defined reversible loss of primordial follicles. These findings support that the maintenance of the oocyte reserve in mammalian ovaries during adulthood involves active input of new oocytes from OSCs. These data also lay a solid foundation for future studies of ovarian biology and disease pathogenesis with unprecedented possibilities, including an understanding of female reproductive aging that accounts for OSC contribution to ovarian function. The specific aims of this proposal are to: 1) establish the physiological roles of OSCs in ovarian aging using novel sg-Tg mice we have developed, in which differentiating OSC daughter cells can be selectively ablated; 2) evaluate glial cell-derived neurotrophic factor (GDNF) and fibroblast growth factor (FGF9) as possible OSC niche factors in stimulating OSC proliferation and suppressing OSC meiotic differentiation, respectively; 3) characterize OSC niches during periods of increased OSC mitotic activity and examine the participation of vascular endothelial cells in niche function; and, 4) develop improved OSC culture conditions by using ovarian somatic cells as feeder cells to recapitulate OSC-niche interaction ex vivo and examine the impact of aging on OSC activity. Ultimately, this information might be used to develop novel and targeted therapeutics that rescue ovarian function through increasing the oocyte reserve by stimulating OSC activity when it would be desirable - such as in patients with premature ovarian failure, in women of advanced maternal age (to postpone age- related ovarian failure and menopause) or in female cancer patients (to rescue their ovarian function and fertility after anti-cancer treatments) - all of these conditions represent increasing

项目概要 干细胞生物学最令人兴奋的领域之一涉及干细胞功能障碍发挥作用的可能性 在与衰老相关的器官功能恶化中发挥核心作用。最近的研究表明，卵原细胞（卵母细胞） 产生）干细胞（OSC）存在于成年哺乳动物的卵巢中。 OSC 的存在提出了以下可能性： 卵巢老化，以含卵母细胞的卵泡的丧失和耗尽为标志，可能同样涉及 干细胞功能逐渐丧失。因此，现在重要的是确定 OSCs 在 卵巢功能与衰老。我的长期目标是确定衰老过程如何对 OSC 产生负面影响 功能，从而使用 OSC 作为模型来深入了解基于干细胞的有机体机制 老化。具体来说，我建议使用我们开发的新型自杀基因转基因（sg-Tg）小鼠模型 过去三年来研究这个。这些小鼠模型的独特之处在于能够区分 OSC 子代 使用自杀基因技术可以选择性地靶向和消除细胞。在我们的初步数据中，我们显示 选择性破坏这些 OSC 分化途径会导致基因定义的可逆性丧失 原始卵泡。这些发现支持哺乳动物卵巢中卵母细胞储备的维持 成年期涉及来自 OSC 的新卵母细胞的主动输入。这些数据也奠定了坚实的基础 卵巢生物学和疾病发病机制的未来研究具有前所未有的可能性，包括 了解女性生殖衰老，解释 OSC 对卵巢功能的贡献。这 该提案的具体目标是：1）利用新颖的方法确定 OSC 在卵巢衰老中的生理作用 我们开发了sg-Tg小鼠，其中分化的OSC子细胞可以被选择性消融； 2） 评估神经胶质细胞源性神经营养因子 (GDNF) 和成纤维细胞生长因子 (FGF9) 作为可能的 OSC 分别刺激 OSC 增殖和抑制 OSC 减数分裂分化的生态位因子； 3） 描述 OSC 有丝分裂活动增加期间的 OSC 生态位并检查 血管内皮细胞的生态位功能； 4) 利用卵巢改善 OSC 培养条件 体细胞作为饲养细胞，在体外重现 OSC-生态位相互作用，并检查衰老对细胞的影响 OSC 活动。最终，这些信息可能会被用来开发新颖的、有针对性的疗法来拯救 通过在需要时刺激 OSC 活性来增加卵母细胞储备，从而发挥卵巢功能 - 例如卵巢早衰患者、高龄产妇（以推迟年龄- 相关的卵巢功能衰竭和更年期）或女性癌症患者（以挽救她们的卵巢功能和 抗癌治疗后的生育能力）-所有这些条件都代表着增加