Macrophage regulation of the spermatogonial stem cell niche

巨噬细胞对精原干细胞生态位的调节

基本信息

批准号：
9924551
负责人：
Tony J. DeFalco
金额：
$ 39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-05-31
项目状态：
已结题

项目摘要

Project Summary/Abstract Defects in tissue stem cell self-renewal and differentiation are linked to organ malformations during fetal development and organ dysfunction in adult life. Despite this wide range of healthcare implications, the cellular and molecular regulation of stem cells is poorly understood, in particular with respect to the microenvironment in which tissue stem cells reside, termed the niche. An excellent model for studying stem cell biology is the mammalian spermatogonial stem cell (SSC) niche, as tight regulation of self-renewal and differentiation is required for the constant production of a large number of gametes over a long reproductive lifespan; imbalances in this process directly contribute to infertility or germ-cell-derived cancers. Despite research efforts, the cellular components of the SSC niche remain largely undefined. Our preliminary data reveal that macrophages are a critical part of the niche required for spermatogenesis. Macrophages are immune cells that are present throughout most organs and are traditionally associated with phagocytosis of foreign pathogens in the innate immune response; however, there is a growing awareness of tissue-specific developmental roles for macrophages. Additionally, several studies have reported that macrophages are located near tissue stem cell niches, but their roles in this biological context are unclear. Therefore, the mechanisms by which macrophages form part of stem cell niches and direct stem cell activity represent a significant knowledge gap in the field. In particular, specific roles for macrophages in the SSC niche have not been previously investigated. This research program will address important unanswered questions in SSC niche biology through three focused goals: 1) to identify the mechanisms used by macrophages to promote SSC differentiation; 2) to determine the signals that recruit macrophages to the stem cell niche; and 3) to define the role of macrophages in coordinating with other somatic cell types, such as Sertoli cells and peritubular myoid cells, to establish and maintain the niche. To accomplish these goals, we will employ: in vivo genetic mouse models; ex vivo culture systems; lineage-specific genomic studies of purified cell populations; and whole organ time-lapse live imaging. These approaches will allow us to obtain an in-depth knowledge of testis stem cell niche function that was previously unattainable. This work will identify novel cellular and molecular mechanisms directing the SSC niche and uncover new paradigms of stem cell biology that are relevant to both development and disease. Ultimately, this research will lead to new insights into the etiology of male infertility and testicular cancer, and aid in the creation of improved diagnostic and treatment methods for these conditions.

项目摘要/摘要组织干细胞的缺陷自我更新和分化与胎儿期间器官畸形有关成人生活中的发展和器官功能障碍。尽管具有广泛的医疗保健意义，但细胞干细胞的分子调节很少了解，特别是相对于微环境其中的组织干细胞驻留，称为利基。研究干细胞生物学的一个绝佳模型是哺乳动物的精子干细胞（SSC）小众，作为对自我更新和分化的严格调节在长期生殖寿命中持续生产大量配子所必需的；此过程中的失衡直接导致不孕症或细菌衍生的癌症。尽管有研究努力，SSC利基市场的细胞成分在很大程度上仍然不确定。我们的初步数据表明巨噬细胞是精子发生所需的利基市场的关键部分。巨噬细胞是免疫细胞在大多数器官中都存在，传统上与外国病原体的吞噬作用有关先天免疫反应；但是，人们对组织特异性发育作用的认识越来越巨噬细胞。此外，一些研究报告说巨噬细胞位于组织干细胞附近利基市场，但它们在这种生物学环境中的作用尚不清楚。因此，巨噬细胞的机制构成干细胞壁ni和直接干细胞活性的一部分代表了该领域的显着知识差距。在先前尚未研究过SSC利基市场中巨噬细胞的特定特定作用。这研究计划将通过三个重点来解决SSC利基生物学中重要的未解决问题目标：1）确定巨噬细胞用于促进SSC分化的机制； 2）确定将巨噬细胞募集到干细胞生态位的信号； 3）定义巨噬细胞在与其他体细胞类型（例如Sertoli细胞和周围肌动物细胞）进行协调，以建立和保持利基市场。为了实现这些目标，我们将采用：体内遗传小鼠模型；离体文化系统；纯化细胞群体的谱系特异性基因组研究；和整个器官延时现场成像。这些方法将使我们能够获得对睾丸干细胞生态位功能的深入了解以前是无法实现的。这项工作将确定引导SSC的新型细胞和分子机制与发育和疾病相关的干细胞生物学的利基市场和新的范式。最终，这项研究将导致对男性不育症和睾丸癌的病因以及有助于为这些疾病改善诊断和治疗方法的改进。