A microphysiological engineered 3D system to the rescue of ovarian follicles

项目摘要 卵泡是卵巢的功能多细胞单位，负责妇女的生育和 卵巢内分泌功能。目前，年轻妇女和青春期前女孩被诊断患有癌症并面临 卵子毒性治疗在保留其生育能力方面的选择有限，首先要冷冻保存卵巢组织 化疗是最有希望的途径。只有原始的和早期的初级卵泡存活下来 超低温保存。为了生长和成熟，卵泡必须被分离并成组培养，因为如果 单独培养。分离的早期卵泡成组培养的翻译潜力有限，因为 队列中不同发育阶段和不同质量的卵泡，因此强调需要 开发成功单独培养早期卵泡的方法。体外卵泡成功率低 发育归因于复杂且鲜为人知的旁分泌和自分泌信号 毛囊中的细胞、邻近的毛囊及其微环境。我们的整体研究目标是：(A) 确定早期卵泡在体外激活和生长的关键因素，(B)建立 分泌因子、下游受体与转录之间的网络和功能关系 因素，以及(C)建立标准化的体外培养系统，促进早期的生长和成熟 单独的毛囊。这项研究的新颖性和意义在于发现了关键 控制和指导卵泡发育最早阶段的因素。A系统的应用 生物学方法研究复杂的多细胞类器官结构中的动态过程，如卵泡， 有可能转化为人类卵泡，并研究其他组织的发育和相互作用 器官和胚胎。

Project Summary Ovarian follicles are the functional multicellular units of the ovary responsible for a woman’s fertility and ovarian endocrine function. Currently, young women and prepubertal girls diagnosed with cancer and facing ovo-toxic treatments have limited options to preserve their fertility, with cryopreservation of ovarian tissue prior to chemotherapy being the most promising route. Only primordial and early-stage primary follicles survive cryopreservation. To grow and mature, follicles have to be isolated and cultured in groups, because they die if cultured individually. Culture of isolated early follicles as groups has limited translational potential, because of different developmental stages and varying quality of follicles in the cohort, thus emphasizing the need to develop approaches to successfully culture early follicles individually. The low success rates of in vitro follicle development are attributed to the complex and poorly understood paracrine and autocrine signaling between the cells in a follicle, neighboring follicles and their microenvironment. Our overall research objectives are: (a) to identify key factors essential for activation and growth of early stage follicles in vitro, (b) to establish networks and functional relationships between secreted factors, downstream receptors and transcription factors, and (c) to create a standardized in vitro culture system that promotes growth and maturation of early follicles individually. The novelty and the significance of the proposed research are in the discovery of key factors that control and direct the earliest stages of ovarian follicle development. Application of a systems biology approach to study dynamic processes in complex multicellular organoid structures, such as follicles, has the potential to translate to human follicles and study the development and interplay in other tissue organoids and embryos.