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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

基本信息

批准号：
9975009
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
项目类别：
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/9975009
关键词：
Adult Androgens Biological Models Biological Process Blood Vessels Cell Differentiation process Cells Coculture Techniques Congenital Abnormality 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 Mesenchymal Mesenchyme Methods 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 Spermatogenesis 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 male health mouse model notch protein novel progenitor reproductive sertoli cell sex determination sex development disorder stem cell niche stem cells steroid hormone tissue stem cells tumor progression tumorigenesis

项目摘要

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/文摘