Reciprocal communication between human neural stem cells and human endothelial cells

人类神经干细胞和人类内皮细胞之间的相互通讯

• 批准号: 10066943
• 负责人: Brenda Gutierrez
• 金额: $ 4.05万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066943
• 关键词: 3-Dimensional; Adopted; Adult; Affect; Animal Model; Astrocytes; B cell differentiation; B-Lymphocytes; Biology; Blood Vessels; Brain; Brain Injuries; Cadherins; Cell Communication; Cell Cycle Kinetics; Cell Therapy; Cells; Coculture Techniques; Communication; Communities; Complex; Data; Development; Educational workshop; Endothelial Cells; Environment; Ephrins; Fellowship; Future; Glial Fibrillary Acidic Protein; Goals; Human; In Vitro; Injury; Integrins; Knowledge; Ligands; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane Proteins; Modeling; N-Cadherin; Neurosciences; Pathway interactions; Phenotype; Physiology; Production; Property; Proteins; Publications; Recovery of Function; Regulation; Research; Research Personnel; Rodent; Rodent Model; Role; Signal Transduction; Stains; System; Technical Expertise; Testing; Therapeutic; Transplantation; Work; adult stem cell; beta catenin; brain cell; cell behavior; cell type; collaborative environment; exosome; extracellular vesicles; human adult stem cell; human disease; immunocytochemistry; improved; insight; intercellular communication; nerve stem cell; neurovascular; notch protein; novel; post stroke; prevent; receptor; relating to nervous system; repaired; scaffold; self-renewal; single-cell RNA sequencing; species difference; stem; stem cell proliferation; stem cells; subventricular zone; supportive environment; symposium; transcriptome; transcriptome sequencing

PROJECT SUMMARY Neural stem/progenitor cells (NSPCs) are in close communication with vessel-forming endothelial cells (ECs) in the developing brain and adult neural stem cell niches such as the subventricular zone. In addition, transplantation of NSPCs stimulates new vessel formation after stroke, leading to improved functional recovery in rodent models. Despite the importance of NSPC and EC interactions, the complex reciprocal communication between NSPCs and ECs is not well understood, especially in humans. Research on the effect of ECs on NSPCs has focused on EC-secreted factors, which regulate NSPC proliferation, differentiation, and self-renewal. However, the role of EC contact on NSPC phenotype and the interaction of human NSPCs and ECs have not been well studied. We demonstrated that human NSPC (hNSPC) contact with human ECs (hECs) stimulates an increase in the percentage of cells expressing both GFAP and Sox2, which are markers for type B cells, the NSPCs of the adult subventricular zone. The first aim of this study is to determine whether hNSPC contact with hECs promotes a type B cell phenotype by characterizing GFAP+/Sox2+ cells found in co-cultures via staining for additional type B cell markers, single cell RNA sequencing, assessment of cell cycle kinetics and differentiation potential. The second aim is to identify mechanisms involved in this hEC contact-mediated change in hNSPC phenotype by focusing on pathways involved in cell-cell communication such as N-cadherin/b-catenin, integrin signaling, Notch signaling, and Eph/ephrin pathways. NSPCs stimulate vessel formation by ECs. However, the mechanisms by which NSPCs stimulate vessel formation are not understood. Preliminary data using a 3D neurovascular model demonstrates that increased human vessel formation is promoted by hNSPC-secreted factors. The third aim is to identify hNSPC-secreted components stimulating hEC vessel formation by assessing hNSPC conditioned media for potential pro-vasculogenic soluble factors and extracellular vesicles and confirming their role in vessel formation by blocking their effects. Studying the interaction between ECs and NSPCs using human cells can provide better insight into the role of their communication in human brain development, regulation of adult stem cell niches, and repair after brain injury. Animal models have been instrumental for progress in research but have translational limitations due to species differences. Using human cells will allow us to study the interaction of both cell types in a system that may more closely resemble human brain physiology but in a less complex environment. Under this fellowship, I will have the opportunity to work with leading researchers at UC Irvine conducting neuroscience, stem cell, and vessel biology research in a collaborative and supportive environment. To expand my technical skills and knowledge, I will attend workshops, seminars, and conferences on topics important for my research. Research findings will be shared with the scientific community and public via conferences and publications.

项目总结