A three-dimensional (3D) organotypic microfluidic model for glioma stem cells - Vascular interactions

Authors

Danh Truong, School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ, USA.
Roberto Fiorelli, Division of Neurobiology, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Eric S. Barrientos, School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ, USA.
Ernesto Luna Melendez, Division of Neurobiology, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Nader Sanai, Division of Neurobiology, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Shwetal Mehta, Division of Neurobiology, Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA. Electronic address: smehta@barrowneuro.org.
Mehdi Nikkhah, School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ, USA. Electronic address: mnikkhah@asu.edu.

Document Type

Article

Abstract

Glioblastoma (GBM) is one of the deadliest forms of cancer. Despite many treatment options, prognosis of GBM remains dismal with a 5-year survival rate of 4.7%. Even then, tumors often recur after treatment. Tumor recurrence is hypothesized to be driven by glioma stem cell (GSC) populations which are highly tumorigenic, invasive, and resistant to several forms of therapy. GSCs are often concentrated around the tumor vasculature, referred to as the vascular niche, which are known to provide microenvironmental cues to maintain GSC stemness, promote invasion, and resistance to therapies. In this work, we developed a 3D organotypic microfluidic platform, integrated with hydrogel-based biomaterials, to mimic the GSC vascular niche and study the influence of endothelial cells (ECs) on patient-derived GSC behavior and identify signaling cues that mediate their invasion and phenotype. The established microvascular network enhanced GSC migration within a 3D hydrogel, promoted invasive morphology as well as maintained GSC proliferation rates and phenotype (Nestin, SOX2, CD44). Notably, we compared migration behavior to in vivo mice model and found similar invasive morphology suggesting that our microfluidic system could represent a physiologically relevant in vivo microenvironment. Moreover, we confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment by utilizing a CXCR4 antagonist (AMD3100), while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Our model presents a potential ex vivo platform for studying the interplay of GSCs with its surrounding microenvironment as well as development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in GSC regulatory mechanisms.

Medical Subject Headings

Animals; Biocompatible Materials (chemistry); Cell Line, Tumor; Cell Movement; Coculture Techniques (instrumentation); Endothelial Cells (pathology); Glioma (blood supply, pathology); Human Umbilical Vein Endothelial Cells; Humans; Hydrogels (chemistry); Lab-On-A-Chip Devices; Mice, Inbred ICR; Microvessels (pathology); Neoplastic Stem Cells (pathology); Stem Cell Niche

Publication Date

4-1-2019

Publication Title

Biomaterials

E-ISSN

1878-5905

Volume

198

First Page

63

Last Page

77

PubMed ID

30098794

Digital Object Identifier (DOI)

10.1016/j.biomaterials.2018.07.048

Recommended Citation

Truong, Danh; Fiorelli, Roberto; Barrientos, Eric S.; Melendez, Ernesto Luna; Sanai, Nader; Mehta, Shwetal; and Nikkhah, Mehdi, "A three-dimensional (3D) organotypic microfluidic model for glioma stem cells - Vascular interactions" (2019). Translational Neuroscience. 1582.
https://scholar.barrowneuro.org/neurobiology/1582