Macrophage regulation of the spermatogonial stem cell niche

巨噬细胞对精原干细胞生态位的调节

• 批准号: 9137899
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137899
• 关键词: Address; Adult; Awareness; Biological; Biology; Cells; Data; Defect; Development; Diagnostic; Disease; Etiology; Fetal Development; Functional disorder; Genetic; Genomics; Germ Cells; Goals; Healthcare; Image; Immune; Immune response; Infertility; Infertility study; Knowledge; Lead; Life; Link; Longevity; Male Infertility; Malignant Neoplasms; Malignant neoplasm of testis; Methods; Molecular; Organ; Phagocytosis; Population; Process; Production; Recruitment Activity; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Somatic Cell; Spermatogenesis; Stem cells; Study models; System; Testis; Time; Tissues; Work; abstracting; cell type; germline stem cells; improved; in vivo; insight; macrophage; malformation; mouse model; novel; pathogen; programs; reproductive; self-renewal; sertoli cell; stem cell biology; stem cell differentiation; stem cell niche

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.

项目概要/摘要 组织干细胞自我更新和分化的缺陷与胎儿时期的器官畸形有关 成人生活中的发育和器官功能障碍。尽管对医疗保健有广泛的影响，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 组织干细胞驻留在其中，称为生态位。研究干细胞生物学的一个优秀模型是 哺乳动物精原干细胞（SSC）生态位，因为自我更新和分化的严格调节 在较长的生殖寿命期间持续产生大量配子所需； 这一过程的不平衡直接导致不孕或生殖细胞衍生的癌症。尽管有研究 尽管付出了努力，SSC 生态位的细胞成分仍然很大程度上未定义。我们的初步数据表明 巨噬细胞是精子发生所需生态位的关键部分。巨噬细胞是免疫细胞 存在于大多数器官中，传统上与​​外来病原体的吞噬作用有关 先天免疫反应；然而，人们越来越认识到组织特异性发育作用 巨噬细胞。此外，一些研究报告称巨噬细胞位于组织干细胞附近 利基，但它们在这种生物学背景中的作用尚不清楚。因此，巨噬细胞的机制 干细胞生态位的一部分和直接干细胞活性代表了该领域的重大知识差距。在 特别是，巨噬细胞在 SSC 生态位中的具体作用尚未被研究过。这 研究计划将通过三个重点领域来解决 SSC 利基生物学中尚未解答的重要问题 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生态位的信号； 3）定义巨噬细胞在 与其他体细胞类型（例如支持细胞和管周肌样细胞）协调，建立和 维持利基市场。为了实现这些目标，我们将采用： 体内遗传小鼠模型；离体培养 系统；纯化细胞群的谱系特异性基因组研究；和整个器官延时直播 成像。这些方法将使我们能够深入了解睾丸干细胞生态位功能 以前是无法实现的。这项工作将确定指导 SSC 的新细胞和分子机制 利基并发现与发育和疾病相关的干细胞生物学的新范例。 最终，这项研究将对男性不育和睾丸癌的病因学产生新的见解，并且 帮助建立针对这些疾病的改进的诊断和治疗方法。