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.

项目摘要/摘要 血管在与细胞分化有关的器官发生中起关键的发育作用 形态发生和干细胞壁ni，除了将氧气和代谢物输入发育的组织外。 血管发育失调与许多先天缺陷有关，与 肿瘤进展和转移。尽管具有这些广泛的人类健康影响，但这种机制 脉管系统在基本生物学过程中的启发性角色是很熟悉的，并且代表了 该领域的主要知识差距。我们最近在小鼠中的工作表明血管间充质串扰 是胎儿睾丸器官发生过程中的重要过程。当男性确定途径在 推定睾丸，内皮细胞迁移到睾丸中形成新的血管网络。 在同一发育阶段的卵巢中不进行重塑。已经提出Sertoli细胞， 睾丸的支撑细胞是睾丸器官发生的主要驱动因素，但是我们最近的工作表明 血管间充质相互作用是睾丸形成中的关键形态发生力。是否有启发性 脉管系统的作用在胎儿睾丸中的其他情况下还不清楚。我们的初步数据揭示了一个新的作用 用于维持Leydig细胞祖细胞（LCS）的实证血管，它们是类固醇生成细胞 生产睾丸激素所需的睾丸间质室，睾丸激素是性的关键马。 分化和成人生育能力。当我们阻止早期胎儿睾丸的血管发育时 维持LC分化和较少的祖细胞，强烈表明血管是一种 LC生态位的关键组成部分。但是，脉管系统的分子和细胞基础 指导能力是未知的。我们的长期目标是了解哪种细胞类型对于 维持LC生态位并发现调节LC分化的分子信号。我们将测试我们的 中心假设是建立和维护需要血管间充质串扰 通过2个特定目的的液晶细分市场：1）描绘构成血管生态基市场所需的细胞类型 LC祖细胞的建立和维护； 2）阐明了基础机制 LC生态位内的内皮 - 促进剂相互作用，重点是内皮细胞之间的Notch信号传导 和间质间质。为了实现这些目标，我们将采用：体内遗传小鼠模型；前体 整个器官培养系统；体外原代细胞共培养技术；和整个器官的延时现场成像。 这些方法将使我们能够发现脉管系统基础的关键分子信号和细胞播放器 在组织干细胞生态位中的重要发育作用，我们预计这将与研究具有直接相关性 性发育障碍（DSD）和复制系统的其他先天缺陷，与Horsene有关 男性不育症和组织发生和肿瘤发生中的血管化相关事件。