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: 10474494
• 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/10474494
• 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(NSPC)与脑干细胞中的血管密切相关 利基和移植后用于治疗神经疾病。这种邻接关系允许 NSPC与形成血液的内皮细胞(ECs)之间存在相当大的相互作用 血管，在这些细胞类型之间创造了相互依赖和复杂的关系。人类 NSPC(HNSPC)和人类EC(HEC)的相互作用还没有得到很好的研究，创造了 知识鸿沟阻碍了我们对人脑功能和损伤后修复的了解。 我们使用了一种组织工程学的方法，用3D支架模拟大脑特性来研究 HNSPC-HEC相互作用。我们发现HEC与hNSPC接触后可诱导GFAP+/ SOX2+细胞，可能为B型成体神经干细胞。B类细胞正在缓慢分裂 防止NSPC池耗尽的NSPC，并可能在受伤后激活以帮助 替换丢失的脑细胞。我们发现hNSPC刺激HEC血管形成(血管生成) 这种作用是通过hNSPC分泌的成分而不是hNSPC与hNSPC的接触来介导的 HECS。这些数据导致了一种假设，即接触HEC促进B型成人神经 HNSPC分泌成分刺激血管时的干细胞表型 在3D壁龛中形成。 我们将通过以下目标来检验这一假设：目标1-确定如何与HECS联系 影响hNSPC；目标2--确定hNSPC分泌成分如何影响人体血管； 目的3-检测hNSPC和HECS是否促进B型成体神经干细胞和血管 活着。通过研究3D组织中hNSPC和HECS之间的关键相互作用 通过设计利基，我们将更好地了解它们的关系如何影响人类的大脑 功能。这一知识可以在未来用于优化hNSPC和hNSPC的联合移植 支架中的HECS重建关键的生态位相互作用，从而形成B细胞和 刺激大脑修复的血管。