Reciprocal communication between human neural stem cells and human endothelial cells - 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.
