Human neural stem cell and endothelial cell reciprocal interactions govern cell function

人类神经干细胞和内皮细胞相互作用控制细胞功能

• 批准号: 10299367
• 负责人: LISA A FLANAGAN
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299367
• 关键词: 3-Dimensional; Adult; Affect; B-Lymphocytes; Biomedical Engineering; Blood Vessels; Brain; Brain Stem; Cell Communication; Cell Transplantation; Cell physiology; Cells; Communication; Complex; Data; Endothelial Cells; Environment; Future; Generations; Glial Fibrillary Acidic Protein; Goals; Human; Image; In Vitro; Injury; Knowledge; Lead; Mediating; Molecular Profiling; Neurologic; Neurons; Neurophysiology - biologic function; Pathway interactions; Patients; Phenotype; Property; Regulation; Rodent; Testing; Therapeutic; Tissue Engineering; Transplantation; brain cell; brain repair; brain tissue; cell type; endothelial stem cell; exosome; extracellular vesicles; human stem cells; in vivo; insight; mechanical properties; migration; nerve stem cell; neurogenesis; novel; post-transplant; prevent; relating to nervous system; repaired; scaffold; self-renewal; single-cell RNA sequencing; stem; stem cell biomarkers; stem cell niche; stem cells; transcriptome; vasculogenesis

Project Summary Neural stem/progenitor cells (NSPCs) lie in close proximity to blood vessels in brain stem cell niches and after transplant to treat neurological conditions. This adjacency allows for considerable interaction between NSPCs and the endothelial cells (ECs) that form blood vessels, creating an interdependent and complex relationship between these cell types. Human NSPC (hNSPC) and human EC (hEC) interactions have not been well studied, creating knowledge gaps that hinder our understanding of human brain function and repair after injury. We used a tissue engineering approach with a a 3D scaffold mimicking brain properties to study hNSPC-hEC interactions. We found hEC contact with hNSPCs induced the formation of GFAP+/ SOX2+ cells, which could be type B adult neural stem cells. Type B cells are slowly dividing NSPCs that prevent depletion of the NSPC pool and may be activated after injury to help replace lost brain cells. We found hNSPCs stimulate hEC vessel formation (vasculogenesis) and this effect is mediated by hNSPC secreted components rather than hNSPC contact with hECs. These data lead to the hypothesis that hEC contact promotes a type B adult neural stem cell phenotype while hNSPC secreted components stimulate human vessel formation in 3D niches. We will test this hypothesis with the following Aims: Aim 1 - determine how contact with hECs affects hNSPCs; Aim 2 - determine how hNSPC secreted components impact human vessels; Aim 3 - test whether hNSPCs and hECs promote type B adult neural stem cells and vessels in vivo. By investigating the crucial interactions between hNSPCs and hECs in 3D tissue engineered niches, we will better understand how their relationship impacts human brain function. This knowledge could be used in the future to optimize co-transplants of hNSPCs and hECs in scaffolds to recreate critical niche interactions leading to formation of type B cells and vessels that stimulate brain repair.

项目摘要 神经干/祖细胞（NSPCs）位于脑干细胞中血管附近 壁龛和移植后治疗神经系统疾病。这种相邻性允许 NSPCs和形成血液的内皮细胞（EC）之间存在相当大的相互作用， 血管，在这些细胞类型之间建立相互依赖和复杂的关系。人类 NSPC（hNSPC）和人EC（hEC）的相互作用尚未得到很好的研究， 知识差距阻碍了我们对人类大脑功能和损伤后修复的理解。 我们使用了一种组织工程方法，用一种模拟大脑特性的3D支架来研究 hNSPC-hEC相互作用。我们发现hEC与hNSPCs的接触诱导了GFAP+/ SOX 2+细胞，可能为B型成体神经干细胞。B型细胞正在缓慢分裂 NSPC可防止NSPC池耗尽，并可能在受伤后被激活以提供帮助 取代失去的脑细胞。我们发现hNSPCs刺激hEC血管形成（血管发生） 这种作用是由hNSPC分泌的成分介导的，而不是hNSPC与 内皮细胞。这些数据导致假设，hEC接触促进B型成人神经细胞增殖。 hNSPC分泌成分刺激人体血管时的干细胞表型 在3D壁龛中形成。 我们将用以下目的来检验这一假设：目的1 -确定如何与hEC接触 目的2 -确定hNSPC分泌的组分如何影响人血管; 目的3 -测试hNSPCs和hECs是否促进B型成体神经干细胞和血管在神经干细胞中的表达。 vivo.通过研究三维组织中hNSPCs和hECs之间的关键相互作用， 工程利基，我们将更好地了解他们的关系如何影响人类大脑 功能这些知识可以在未来用于优化hNSPCs的共移植， 支架中的hEC以重建导致B型细胞形成的关键生态位相互作用， 刺激大脑修复的血管