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

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Emmanuela A Adjei-Sowah, Samantha A O'Connor, Jaimeson Veldhuizen, Costanza Lo Cascio, Christopher Plaisier, Shwetal Mehta, Mehdi Nikkhah

TLDR

  • The study aimed to understand how the perivascular niche (PVN) affects glioblastoma stem cells (GSCs). The PVN is a part of the brain where GSCs live and grow. The study used a special tool called a microfluidic organotypic triculture platform to study the PVN and its effects on GSCs. The platform had three types of cells: endothelial cells, astrocytes, and GSCs. The study found that both endothelial cells and astrocytes made GSCs more invasive, meaning they were better at moving through the brain. The study also found that a specific pair of molecules called SAA1-FPR1 was involved in the movement of GSCs towards the PVN. The study highlights the importance of understanding how the PVN affects GSCs and how this knowledge can be used to develop new treatments for glioblastoma.

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.

Overview

  • The study aims to investigate the impact of the perivascular niche (PVN) on glioblastoma stem cells (GSCs) using an organotypic triculture microfluidic model. The hypothesis being tested is that the PVN serves as a safe haven for GSCs and drives their treatment resistance and stemness. The methodology used for the experiment includes the development of a triculture platform comprised of endothelial cells (ECs), astrocytes, and GSCs. The study investigates GSC invasion, proliferation, and stemness in this triculture platform. The primary objective of the study is to identify the ligand-receptor pairs involved in chemotactic mechanisms of GSCs in the PVN.

Comparative Analysis & Findings

  • The study found that both ECs and astrocytes significantly increased the invasiveness of GSCs in the triculture platform. The study also identified 15 ligand-receptor pairs using single-cell RNAseq with putative chemotactic mechanisms of GSCs. Notably, the ligand-receptor pair SAA1-FPR1 was demonstrated to be involved in chemotactic invasion of GSCs toward the PVN.

Implications and Future Directions

  • The study highlights the importance of understanding cellular interactions in the PVN that drive GSC treatment resistance and stemness. The organotypic triculture microfluidic model presented in the study can be used for therapeutic development and discovery of molecular mechanisms driving GSC biology. Future research directions could include the investigation of the role of other cell types in the PVN on GSC behavior and the development of targeted therapies based on the identified ligand-receptor pairs.
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