Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells

Abstract

Endogenous electric fields modulate many physiological processes by promoting directional migration, a process known as galvanotaxis. Despite the importance of galvanotaxis in development and disease, the mechanism by which cells sense and migrate directionally in an electric field remains unknown. Here, we show that electrophoresis of cell surface heparan sulfate (HS) critically regulates this process. HS was found to be localized at the anode-facing side in fetal neural progenitor cells (fNPCs), fNPCderived astrocytes and brain tumor-initiating cells (BTICs), regardless of their direction of galvanotaxis. Enzymatic removal of HS and other sulfated glycosaminoglycans significantly abolished or reversed the cathodic response seen in fNPCs and BTICs. Furthermore, Slit2, a chemorepulsive ligand, was identified to be colocalized with HS in forming a ligand gradient across cellular membranes. Using both imaging and genetic modification, we propose a novel mechanism for galvanotaxis in which electrophoretic localization of HS establishes cell polarity by functioning as a co-receptor and provides repulsive guidance through Slit-Robo signaling.

Voltage-gated ion channels mediate the electrotaxis of glioblastoma cells in a hybrid PMMA/PDMS microdevice

“…Both T98G cells and U-251MG cells are categorized as mesenchymal type glioblastoma 37,38 , however, their electrotactic responses are completely different. Similar results are reported in the electrotaxis of glioblastoma cells and spheroids 15,16,19,39 and lung adenocarcinoma 51 , showing that although molecular and surface marker makeups of the cell lines are similar, their electrotaxis responses can be completely different. The opposite electrotaxis results may reflect the fundamental heterogeneity among glioblastoma cells which has been speculated to contribute to the recurrence and therapeutic resistance after anti-tumor therapy [52][53][54][55][56] .…”

“…The adhesion and electrotaxis of T98G and U-251MG glioblastoma cell lines on various ECMs are tested in a double-layer hybrid multiple electric field chip (HMEFC) based on the hybrid PMMA/PDMS design approach 17 (Supplementary TABLE. S.1). The migration directedness, speed, and morphology of glioblastoma cells (see details in section IV.D) are quantitatively analyzed by a machine learning-based single cell segmentation and tracking software from stain-free phase contrast microscopy 30 While standard poly(D-lysine) (PDL) and various combinations of poly(L-ornithine) (PLO) and laminin have been used for glioblastoma electrotaxis 16,39 , the adhesion and electrotaxis of T98G and U-251MG are not always are not always consistent and reproducible as shown in Supplementary FIG. S.2 and FIG.…”

“…A weak endogenous electric current has been shown to serve as a guidance cue for neuroblast migration from the subventricular zone in mouse 13 , a region speculated as the origin of glioma tumorigenesis 14 . Thus, the physiological a) amy.shen@oist.jp electric fields in the brain may play an important role in mediating the glioma tumorigenesis and invasion [15][16][17][18][19] . Cells sense the electric field by bioelectrical activation of voltage-sensitive proteins, mechanosensing due to electrokinetic phenomena, or activated chemical signaling due to electrokinetically polarized membrane receptors ( Supplementary FIG.…”

Novel Electrode Designs for Neurostimulation in Regenerative Medicine: Activation of Stem Cells

“…This galvanotactic response can involve the electrophoresis of charged membrane proteins following electrical stimulation, which creates a ligand gradient along the cell membrane, thereby generating asymmetry within the cell. 23 Another response to the EF is the polarization of charged molecules within the cell, which can lead to asymmetry by binding and blocking channels on the cell surface. 22 An equally plausible hypothesis is the presence of multiple EF-sensing mechanisms and signaling cascades that could, in theory, underlie migration in opposite directions from a resulting ''tug-of-war'' between mechanisms within a single cell.…”

The Literature Review of Electricity Effects on Cell Physiology and Related New Electrical Treatment Modalities

“…The only side effect was mild contact dermatitis. (TT fields = tumor treating fields) (36,37,38,39,40,41) TTF is selectively toxic to proliferating cells via an anti-mitotic mechanism has been widely reported. (42) This may prevent damage to other cells.…”