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Co-culture of Glioblastoma Stem-like Cells on Patterned Neurons to Study Migration and Cellular Interactions
Published on: February 24, 2021
Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells
Yu-Ja Huang1,2, Gwendolyn Hoffmann1,2, Benjamin Wheeler1,2
1Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Abstract:
Galvanotaxis is a complex process that represents the collective outcome of various contributing mechanisms, including asymmetric ion influxes, preferential activation of voltage-gated channels, and electrophoretic redistribution of membrane components. While a large number of studies have focused on various up- and downstream signaling pathways, little is known about how the surrounding microenvironment may interact and contribute to the directional response. Using a customized galvanotaxis chip capable of carrying out experiments in both two- and three-dimensional microenvironments, we show that cell-extracellular matrix (ECM) interactions modulate the galvanotaxis of brain tumor initiating cells (BTICs). Five different BTICs across three different glioblastoma subtypes were examined and shown to all migrate toward the anode in the presence of a direct-current electric field (dcEF) when cultured on a poly-L-ornithine/laminin coated surface, while the fetal-derived neural progenitor cells (fNPCs) migrated toward the cathode. Interestingly, when embedded in a 3D ECM composed of hyaluronic acid and collagen, BTICs exhibited opposite directional response and migrated toward the cathode. Pharmacological inhibition against a panel of key molecules involved in galvanotaxis further revealed the mechanistic differences between 2- and 3D galvanotaxis in BTICs. Both myosin II and phosphoinositide 3-kinase (PI3K) were found to hold strikingly different roles in different microenvironments.
Insights
Brain tumor initiating cells (BTICs) change their directional migration (galvanotaxis) in response to electric fields when moving from 2D to 3D environments. Cell-extracellular matrix interactions significantly alter this response.
Area of Science:
- Cellular biology
- Neuro-oncology
- Biophysics
Background:
- Galvanotaxis, or directed cell migration in response to electric fields, is crucial for biological processes.
- Existing research on galvanotaxis primarily focuses on intracellular signaling pathways.
- The influence of the microenvironment on cell galvanotaxis remains largely unexplored.
Purpose of the Study:
- To investigate how the microenvironment, specifically cell-extracellular matrix (ECM) interactions, modulates the galvanotaxis of brain tumor initiating cells (BTICs).
- To compare the galvanotactic response of BTICs in two-dimensional (2D) versus three-dimensional (3D) microenvironments.
- To elucidate the mechanistic differences underlying galvanotaxis in distinct microenvironmental contexts.
Main Methods:
- Utilized a custom-designed galvanotaxis chip for experiments in both 2D and 3D microenvironments.
- Examined galvanotaxis of five different BTIC lines from three glioblastoma subtypes and fetal-derived neural progenitor cells (fNPCs).
- Cultured cells on poly-L-ornithine/laminin coated surfaces (2D) and embedded them in 3D ECM (hyaluronic acid and collagen).
- Administered pharmacological inhibitors targeting key galvanotaxis molecules for mechanistic studies.
Main Results:
- BTICs migrated towards the anode in a direct-current electric field (dcEF) on 2D surfaces, while fNPCs migrated towards the cathode.
- BTICs embedded in 3D ECM exhibited an inverse response, migrating towards the cathode.
- Pharmacological inhibition revealed distinct roles for myosin II and phosphoinositide 3-kinase (PI3K) in 2D versus 3D galvanotaxis of BTICs.
Conclusions:
- Cell-ECM interactions significantly modulate BTIC galvanotaxis, altering their directional response based on microenvironmental dimensionality.
- The study highlights critical mechanistic differences in galvanotaxis between 2D and 3D environments for BTICs.
- Findings underscore the importance of considering the microenvironment when studying cell migration and developing therapeutic strategies for brain tumors.
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