Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single-Cell Resolution using a Microfluidic Tumor Microenvironment Model

Authors

Emmanuela A. Adjei-Sowah, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287-9709, USA.
Samantha A. O'Connor, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287-9709, USA.
Jaimeson Veldhuizen, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287-9709, USA.
Costanza Lo Cascio, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W Thomas Rd, Phoenix, AZ, 85013, USA.
Christopher Plaisier, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287-9709, USA.
Shwetal Mehta, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W Thomas Rd, Phoenix, AZ, 85013, USA.
Mehdi Nikkhah, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287-9709, USA.

Document Type

Article

Abstract

The perivascular niche (PVN) is a glioblastoma tumor microenvironment (TME) that serves as a safe haven for glioma stem cells (GSCs), and acts as a reservoir that inevitably leads to tumor recurrence. Understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness is crucial to develop lasting therapies for glioblastoma. The limitations of in vivo models and in vitro assays have led to critical knowledge gaps regarding the influence of various cell types in the PVN on GSCs behavior. This study developed an organotypic triculture microfluidic model as a means to recapitulate the PVN and study its impact on GSCs. This triculture platform, comprised of endothelial cells (ECs), astrocytes, and GSCs, is used to investigate GSC invasion, proliferation and stemness. Both ECs and astrocytes significantly increased invasiveness of GSCs. This study futher identified 15 ligand-receptor pairs using single-cell RNAseq with putative chemotactic mechanisms of GSCs, where the receptor is up-regulated in GSCs and the diffusible ligand is expressed in either astrocytes or ECs. Notably, the ligand-receptor pair SAA1-FPR1 is demonstrated to be involved in chemotactic invasion of GSCs toward PVN. The novel triculture platform presented herein can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology.

Keywords

glioblastoma, invasion, perivascular niche, transcriptomics, tumor microenvironment

Medical Subject Headings

Brain Neoplasms (metabolism, pathology); Endothelial Cells (metabolism, pathology); Glioblastoma (metabolism, pathology); Glioma (blood supply, metabolism, pathology); Humans; Ligands; Microfluidics; Neoplasm Recurrence, Local (metabolism, pathology); Neoplastic Stem Cells (metabolism, pathology); Tumor Microenvironment

Publication Date

7-1-2022

Publication Title

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

E-ISSN

2198-3844

Volume

9

Issue

21

First Page

e2201436

PubMed ID

35619544

Digital Object Identifier (DOI)

10.1002/advs.202201436

Recommended Citation

Adjei-Sowah, Emmanuela A.; O'Connor, Samantha A.; Veldhuizen, Jaimeson; Lo Cascio, Costanza; Plaisier, Christopher; Mehta, Shwetal; and Nikkhah, Mehdi, "Investigating the Interactions of Glioma Stem Cells in the Perivascular Niche at Single-Cell Resolution using a Microfluidic Tumor Microenvironment Model" (2022). Translational Neuroscience. 2264.
https://scholar.barrowneuro.org/neurobiology/2264