Exploring vascular-mesenchymal interactions in the stem cell niche

探索干细胞生态位中的血管间质相互作用

• 批准号: 9792268
• 负责人: Tony J. DeFalco
• 金额: $ 32.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792268
• 关键词: Address; Adult; Androgens; Biological Models; Biological Process; Blood Vessels; Cell Differentiation process; Cells; Coculture Techniques; Congenital Abnormality; Cues; Culture Techniques; Data; Defect; Development; Endothelial Cells; Endothelium; Equilibrium; Etiology; Event; Fertility; Fetal Development; Genetic; Goals; Gonadal structure; Health; Hormones; Human; Image; In Vitro; Instruction; Knowledge; Lead; Ligands; Link; Longitudinal Studies; Maintenance; Male Infertility; Mediating; Mesenchymal; Mesenchyme; Methods; Modeling; Molecular; Morphogenesis; Mus; Neoplasm Metastasis; Organ; Organ Culture Techniques; Organogenesis; Ovary; Oxygen; Pathway interactions; Play; Process; Production; Publications; Publishing; Regulation; Reproductive system; Research; Role; Sexual Development; Signal Transduction; Source; Stem cells; Supporting Cell; System; Testing; Testis; Testosterone; Time; Tissues; Undifferentiated; Vascular remodeling; Vascularization; Work; cell type; fetal; in vivo; insight; interstitial; interstitial cell; leydig interstitial cell; male; mouse model; notch protein; novel; progenitor; reproductive; sertoli cell; sex determination; sex development disorder; stem; stem cell niche; steroid hormone; tumor progression; tumorigenesis

Project Summary/Abstract Blood vessels play critical developmental roles in organogenesis related to cellular differentiation, tissue morphogenesis, and stem cell niches, in addition to delivering oxygen and metabolites to developing tissues. Dysregulation of vascular development is associated with a number of birth defects and is intimately linked to tumor progression and metastasis. In spite of these broad human health implications, the mechanisms that underlie vasculature’s instructive roles in essential biological processes are poorly understood and represent a major knowledge gap in the field. Our recent work in mice demonstrated that vascular-mesenchymal crosstalk is a vital process during fetal testis organogenesis. When the male sex determination pathway is triggered in the presumptive testis, endothelial cells migrate into the testis to form new vascular networks. Interestingly, vascular remodeling does not occur in the ovary at the same developmental stage. It has been proposed that Sertoli cells, the supporting cells of the testis, are the main drivers of testis organogenesis, but our recent work showed that vascular-mesenchymal interactions are a critical morphogenetic force in testis formation. Whether instructive roles for vasculature exist in other contexts in the fetal testis is unclear. Our preliminary data reveal a novel role for testicular vasculature in maintaining progenitors for Leydig cells (LCs), which are steroidogenic cells in the testis interstitial compartment required for the production of testosterone, a critical hormone for sexual differentiation and adult fertility. When we blocked vascular development of the early fetal testis, supernumerary LCs differentiated and fewer progenitor cells were maintained, strongly suggesting that blood vessels are a critical component of the LC niche. However, the molecular and cellular underpinnings of vasculature’s instructive capacity are unknown. Our long-term goals are to understand which cell types are essential for maintaining the LC niche and to uncover the molecular signals that regulate LC differentiation. We will test our central hypothesis that vascular-mesenchymal crosstalk is required for the establishment and maintenance of the LC niche through 2 specific aims: 1) to delineate the cell types that comprise the vascular niche required for the establishment and maintenance of LC progenitors; and 2) to elucidate the molecular mechanisms underlying endothelial-progenitor interactions within the LC niche, focusing on Notch signaling between endothelial cells and interstitial mesenchyme. To accomplish these aims, we will employ: in vivo genetic mouse models; ex vivo whole organ culture systems; in vitro primary cell co-culture techniques; and whole organ time-lapse live imaging. These approaches will allow us to uncover key molecular signals and cellular players that underlie vasculature’s vital developmental role in a tissue stem cell niche, which we anticipate will have direct relevance for the study of disorders of sexual development (DSDs) and other birth defects of the reproductive system, hormone-related male infertility, and vascularization-associated events in organogenesis and tumorigenesis.

项目总结/摘要 血管在与细胞分化、组织分化和细胞分化相关的器官发生中起着关键的发育作用。 形态发生和干细胞小生境，以及向发育中的组织输送氧气和代谢物。 血管发育失调与许多出生缺陷有关，并与以下因素密切相关： 肿瘤进展和转移。尽管存在这些广泛的人类健康影响， 血管系统在基本生物学过程中的指导作用尚不清楚， 这一领域的知识差距很大。我们最近在小鼠中的研究表明， 是胎儿睾丸器官发生的重要过程。当男性性别决定途径被触发时， 在假定的睾丸中，内皮细胞迁移到睾丸中以形成新的血管网络。有趣的是， 在同一发育阶段的卵巢中不发生重构。有人提出支持细胞， 睾丸的支持细胞是睾丸器官发生的主要驱动力，但我们最近的研究表明， 血管-间质相互作用是睾丸形成中的关键形态发生力。是否具有指导意义 血管系统在胎儿睾丸中的其他作用尚不清楚。我们的初步数据揭示了一个新的角色 睾丸血管系统在维持Leydig细胞（LC）祖细胞中的作用，Leydig细胞是睾丸中的类固醇生成细胞， 睾丸间质隔室需要产生睾酮，睾酮是性行为的关键激素 分化和成株育性。当我们阻断早期胎儿睾丸的血管发育时， LC分化和较少的祖细胞被维持，强烈表明血管是一个重要的细胞。 LC利基的关键组成部分。然而，血管系统的分子和细胞基础 教育能力是未知的。我们的长期目标是了解哪些细胞类型对 维持LC生态位并揭示调节LC分化的分子信号。我们将测试我们的 中心假设，即血管间质串扰是建立和维持 通过2个具体目标来描述LC生态位：1）描绘包括血管生态位所需的细胞类型， LC祖细胞的建立和维持; 2）阐明LC祖细胞的分子机制 LC生态位内的内皮-祖细胞相互作用，重点关注内皮细胞之间的Notch信号传导 和间质间充质。为了实现这些目标，我们将采用：体内遗传小鼠模型; 全器官培养系统;体外原代细胞共培养技术;和全器官延时实时成像。 这些方法将使我们能够揭示关键的分子信号和细胞的球员，血管系统的基础， 在组织干细胞生态位中起着至关重要的发育作用，我们预计这将与这项研究直接相关。 性发育障碍和其他生殖系统先天缺陷、与生殖系统有关的 男性不育，以及器官发生和肿瘤发生中的血管化相关事件。