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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/摘要组织干细胞自我更新和分化缺陷与胎儿器官畸形有关成人生活中的发育和器官功能障碍。尽管存在广泛的医疗保健影响，但细胞对干细胞的分子调控知之甚少，特别是在微环境方面。组织干细胞驻留的地方，被称为利基。研究干细胞生物学的一个很好的模型是哺乳动物精原干细胞(SSC)的生态位，因为自我更新和分化的严格调控是在较长的生殖寿命内持续产生大量配子所需的；这一过程中的不平衡直接导致不孕不育或生殖细胞来源的癌症。尽管有研究在这方面的努力中，SSC生态位的细胞构成在很大程度上仍未确定。我们的初步数据显示巨噬细胞是精子发生所需的生态位的关键部分。巨噬细胞是一种免疫细胞存在于大多数器官中，传统上与吞噬外来病原体有关与生俱来的免疫反应；然而，人们越来越意识到组织特定的发育作用巨噬细胞。此外，一些研究报道巨噬细胞位于组织干细胞附近。但它们在这一生物学背景下的作用尚不清楚。因此，巨噬细胞形成干细胞利基的一部分和干细胞的直接活性代表着该领域的重大知识差距。在……里面特别是，巨噬细胞在SSc生态位中的具体作用以前还没有被研究过。这研究计划将通过三个重点关注的问题来解决SSC生态位生物学中尚未回答的重要问题目标：1)确定巨噬细胞促进SSC分化的机制；2)确定将巨噬细胞招募到干细胞巢中的信号；以及3)确定巨噬细胞在与其他体细胞类型，如支持细胞和管周肌样细胞协调，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；体外培养系统；纯化细胞群体的特定谱系基因组研究；以及整个器官的延时存活成像。这些方法将使我们能够深入了解睾丸干细胞的利基功能以前是无法企及的。这项工作将确定指导SSC的新的细胞和分子机制并发现与发育和疾病相关的干细胞生物学的新范例。最终，这项研究将为男性不育和睾丸癌的病因学带来新的见解，以及帮助创建针对这些疾病的改进的诊断和治疗方法。