Guided Migration of Neural Stem Cells Derived from Human Embryonic Stem Cells by an Electric Field

Institute for Regenerative Cures, University of California Davis School of Medicine, California 95817, USA.
Stem Cells (Impact Factor: 6.52). 02/2012; 30(2):349-55. DOI: 10.1002/stem.779
Source: PubMed


Small direct current (DC) electric fields (EFs) guide neurite growth and migration of rodent neural stem cells (NSCs). However, this could be species dependent. Therefore, it is critical to investigate how human NSCs (hNSCs) respond to EF before any possible clinical attempt. Aiming to characterize the EF-stimulated and guided migration of hNSCs, we derived hNSCs from a well-established human embryonic stem cell line H9. Small applied DC EFs, as low as 16 mV/mm, induced significant directional migration toward the cathode. Reversal of the field polarity reversed migration of hNSCs. The galvanotactic/electrotactic response was both time and voltage dependent. The migration directedness and distance to the cathode increased with the increase of field strength. (Rho-kinase) inhibitor Y27632 is used to enhance viability of stem cells and has previously been reported to inhibit EF-guided directional migration in induced pluripotent stem cells and neurons. However, its presence did not significantly affect the directionality of hNSC migration in an EF. Cytokine receptor [C-X-C chemokine receptor type 4 (CXCR4)] is important for chemotaxis of NSCs in the brain. The blockage of CXCR4 did not affect the electrotaxis of hNSCs. We conclude that hNSCs respond to a small EF by directional migration. Applied EFs could potentially be further exploited to guide hNSCs to injured sites in the central nervous system to improve the outcome of various diseases.

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Available from: Xiu-Zhen Zhang, Oct 13, 2014
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    • "The ROCK inhibitor Y27632 enhanced the viability of stem cells and inhibited EF-guided directional migration in induced pluripotent stem cells and neurons. However, it did not significantly affect the directionality of hNSC migration in an EF (Feng et al., 2012). "
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    ABSTRACT: In peripheral nervous systems, Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. Following spinal cord injury, Schwann cells regenerate and migrate to the lesion and are involved in the spinal cord regeneration process. Transplantation of Schwann cells into injured neural tissue results in enhanced spinal axonal regeneration. Effective directional migration of Schwann cells is critical in the neural regeneration process. In this study, we report that Schwann cells migrate anodally in an applied electric field (EF). The directedness and displacement of anodal migration increased significantly when the strength of the EF increased from 50 mV/mm to 200 mV/mm. The EF did not significantly affect the cell migration speed. To explore the genes and signaling pathways that regulate cell migration in EFs, we performed a comparative analysis of differential gene expression between cells stimulated with an EF (100 mV/mm) and those without using next-generation RNA sequencing, verified by RT-qPCR. Based on the cut-off criteria (FC > 1.2, q < 0.05), we identified 1,045 up-regulated and 1,636 down-regulated genes in control cells versus EF-stimulated cells. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that compared to the control group, 21 pathways are down-regulated, while 10 pathways are up-regulated. Differentially expressed genes participate in multiple cellular signaling pathways involved in the regulation of cell migration, including pathways of regulation of actin cytoskeleton, focal adhesion, and PI3K-Akt. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 07/2015; 230(7). DOI:10.1002/jcp.24897 · 3.84 Impact Factor
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    • "Furthermore , as part of multidisciplinary approaches to develop the guided migration of stem/progenitor cells strategically, it is potentially beneficial to use EF treatment in combination with stem cell therapy to facilitate neuro-regeneration and repair for a variety of neurodegenerative diseases and CNS injuries. Direct current (DC) electrical field (EF) is an effective cue to guide neurite growth and the migration of neurons and other types of cells (Zhao et al., 2006; Meng et al., 2011; Feng et al., 2012). Unfortunately, the response of ventral midbrain progenitors to an EF cannot be deduced from previous publications, because the guidance effect of EFs for cell migration and neurite growth has significant interspecies difference and is cell type dependent. "
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    ABSTRACT: Neural progenitor cell (NPC) replacement therapy is a promising treatment for neurodegenerative disorders including Parkinson's disease (PD). It requires a controlled directional migration and integration of NPCs, for example dopaminergic (DA) progenitor cells, into the damaged host brain tissue. There is, however, only limited understanding of how to regulate the directed migration of NPCs to the diseased or damaged brain tissues for the repair and regeneration. The aims of this study are to explore the possibility of using a physiological level of electrical stimulation to regulate the directed migration of ventral midbrain NPCs (NPC(vm)), and to investigate its potential regulation via GSK3β and associated downstream effectors. We tested the effects of direct-current (DC) electric fields (EFs) on the migration behaviors of the NPC(vm). A DC EF induced directional cell migration towards the cathode, namely electrotaxis. Reversal of the EF polarity triggered a sharp reversal of NPC(vm) electrotaxis. The electrotactic response was both time and EF voltage dependent. Pharmacologically inhibiting the canonical Wnt / GSK3β pathway significantly reduced the electrotactic response of NPC(vm), which is associated with the down-regulation of GSK3β phosphorylation, β-catenin activation and CLASP2 expression. This was further proved by RNA interference of GSK3β, which also showed a significantly reduced electrotactic response in association with reduced β-catenin activation and CLASP2 expression. In comparison, RNA interference of β-catenin slightly reduced electrotactic response and CLASP2 expression. Both pharmacological inhibition of Wnt / GSK3β and RNA interference of GSK3β / β-catenin clearly reduced the asymmetric redistribution of CLASP2 and its co-localization with α-tubulin. These results suggest that Wnt / GSK3β signaling contributes to the electrotactic response of NPC(vm) through the coordination of GSK3β phosphorylation, β-catenin activation, CLASP2 expression and asymmetric redistribution to the leading edge of the migrating cells.
    Experimental Neurology 09/2014; 263. DOI:10.1016/j.expneurol.2014.09.014 · 4.70 Impact Factor
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    • "characteristic of microanalytical EK methods is that intact microorganisms can be analyzed. For example electrotaxis, the movement of adherent cells in response to an electric field, has been used to guide the migration of neural stem cells (Feng et al. 2012) and lung cancer cells in 3D scaffolds (Sun et al. 2012). Electrorotation is another important electrokinetic method employed successfully for cell assessment that allows extracting dielectric properties (Voyer et al. 2010). "
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