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

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. STEM CELLS 2012; 30:349–355.

[1]  C. McCaig,et al.  Temporally and spatially coordinated roles for Rho, Rac, Cdc42 and their effectors in growth cone guidance by a physiological electric field , 2006, Journal of Cell Science.

[2]  V. Gallo,et al.  Overexpression of the Epidermal Growth Factor Receptor Confers Migratory Properties to Nonmigratory Postnatal Neural Progenitors , 2005, The Journal of Neuroscience.

[3]  B. Heng.  Effect of Rho-associated kinase (ROCK) inhibitor Y-27632 on the post-thaw viability of cryopreserved human bone marrow-derived mesenchymal stem cells. , 2009, Tissue & cell.

[4]  Jack M Parent,et al.  Rat forebrain neurogenesis and striatal neuron replacement after focal stroke , 2002, Annals of neurology.

[5]  L. Yao,et al.  Small applied electric fields guide migration of hippocampal neurons , 2008, Journal of cellular physiology.

[6]  Ronald A. Li,et al.  Electrically Guiding Migration of Human Induced Pluripotent Stem Cells , 2010, Stem Cell Reviews and Reports.

[7]  Kenneth R. Robinson,et al.  Electric field effects on human spinal injury: Is there a basis in the in vitro studies? , 2008, Developmental neurobiology.

[8]  L. Ou,et al.  Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  Samia J. Khoury,et al.  Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Min Zhao,et al.  Electrical signals polarize neuronal organelles, direct neuron migration, and orient cell division , 2009, Hippocampus.

[11]  F. Gage,et al.  PI3K mediated electrotaxis of embryonic and adult neural progenitor cells in the presence of growth factors , 2011, Experimental Neurology.

[12]  Marius Wernig,et al.  In vitro differentiation of transplantable neural precursors from human embryonic stem cells , 2001, Nature Biotechnology.

[13]  L. Wahlberg,et al.  Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury. , 2004, Journal of neurosurgery.

[14]  O. Lindvall,et al.  Stem cell therapy for human neurodegenerative disorders–how to make it work , 2004, Nature Medicine.

[15]  Jenea M. Bin,et al.  A central role for RhoA during oligodendroglial maturation in the switch from Netrin‐1‐mediated chemorepulsion to process elaboration , 2010, Journal of neurochemistry.

[16]  V. Balasubramaniyan,et al.  The role of CXC chemokine ligand (CXCL)12‐CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour , 2009, Neuropathology and applied neurobiology.

[17]  M Chopp,et al.  Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia , 2001, Neuroscience.

[18]  Min Zhao,et al.  Electrotaxis and wound healing: experimental methods to study electric fields as a directional signal for cell migration. , 2009, Methods in molecular biology.

[19]  Yen-Chung Chen,et al.  Rho Kinases Regulate the Renewal and Neural Differentiation of Embryonic Stem Cells in a Cell Plating Density–Dependent Manner , 2010, PloS one.

[20]  J V Forrester,et al.  Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent. , 1996, Journal of cell science.

[21]  S. Paek,et al.  Effects of human neural stem cell transplantation in canine spinal cord hemisection , 2009, Neurological research.

[22]  B. Will,et al.  Injections of fluid or septal cell suspension grafts into the dentate gyrus of rats induce granule cell degeneration , 1993, Neuroscience Letters.

[23]  F. Gage,et al.  Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Slovak,et al.  Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immunodeficient mice. , 2007, Stem cells and development.

[25]  C. McCaig,et al.  The direction of growth of differentiating neurones and myoblasts from frog embryos in an applied electric field. , 1981, The Journal of physiology.

[26]  D. Rancourt,et al.  The ROCK inhibitor Y-27632 enhances the survival rate of human embryonic stem cells following cryopreservation. , 2008, Stem cells and development.

[27]  O. Lindvall,et al.  Cell Number and Timing of Transplantation Determine Survival of Human Neural Stem Cell Grafts in Stroke-Damaged Rat Brain , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[28]  P. Cormie,et al.  Embryonic zebrafish neuronal growth is not affected by an applied electric field in vitro , 2007, Neuroscience Letters.

[29]  Min Zhao,et al.  Controlling cell behavior electrically: current views and future potential. , 2005, Physiological reviews.

[30]  K. R. Robinson,et al.  The growth of PC12 neurites is biased towards the anode of an applied electrical field. , 1994, Journal of neurobiology.

[31]  S. Khaldoyanidi.  Directing stem cell homing. , 2008, Cell stem cell.

[32]  M. Poo,et al.  Orientation of neurite growth by extracellular electric fields , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  Hossein Baharvand,et al.  Human embryonic stem cell-derived neural precursor transplants in collagen scaffolds promote recovery in injured rat spinal cord. , 2009, Cytotherapy.

[34]  Donald S. Prough,et al.  Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury , 2006, Experimental Neurology.

[35]  A. Srivastava,et al.  Transplanted Embryonic Stem Cells Successfully Survive, Proliferate, and Migrate to Damaged Regions of the Mouse Brain , 2006, Stem cells.

[36]  Brian J Cummings,et al.  Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function , 2006, Neurological research.

[37]  Min Zhao,et al.  Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo , 2006, Nature Protocols.

[38]  Min Zhao,et al.  A time‐lapse and quantitative modelling analysis of neural stem cell motion in the absence of directional cues and in electric fields , 2010, Journal of neuroscience research.

[39]  Seung-Ki Kim,et al.  Human Neural Stem Cells Target Experimental Intracranial Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor Regression , 2006, Clinical Cancer Research.

[40]  Jian Zhu,et al.  Transplantation of MSCs in combination with netrin-1 improves neoangiogenesis in a rat model of hind limb ischemia. , 2011, The Journal of surgical research.

[41]  C. McCaig,et al.  Electric field‐induced orientation of rat hippocampal neurones in vitro , 1992, Experimental physiology.

[42]  K. Jin,et al.  Delayed transplantation of human neural precursor cells improves outcome from focal cerebral ischemia in aged rats , 2010, Aging cell.

[43]  Min Zhao,et al.  Electrical fields in wound healing-An overriding signal that directs cell migration. , 2009, Seminars in cell & developmental biology.

[44]  Richard J. Miller,et al.  CXCR4 signaling in the regulation of stem cell migration and development , 2008, Journal of Neuroimmunology.

[45]  Q. Wan,et al.  Direct‐Current Electrical Field Guides Neuronal Stem/Progenitor Cell Migration , 2008, Stem cells.

[46]  Mi Hyun Kim,et al.  Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[47]  Brian J Cummings,et al.  Human Neural Stem Cells Differentiate and Promote Locomotor Recovery in an Early Chronic Spinal coRd Injury NOD-scid Mouse Model , 2010, PloS one.

[48]  J. Naegele,et al.  CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus , 2010, PloS one.

[49]  Yang D. Teng,et al.  Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells , 2007, Proceedings of the National Academy of Sciences.

[50]  M. Chopp,et al.  Stromal Cell-Derived Factor 1α Mediates Neural Progenitor Cell Motility after Focal Cerebral Ischemia , 2006 .

[51]  T. Yasuhara,et al.  Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease , 2006, The Journal of Neuroscience.

[52]  M. Chopp,et al.  Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[53]  M. Akimoto,et al.  The Simultaneous Treatment of MMP‐2 Stimulants in Retinal Transplantation Enhances Grafted Cell Migration into the Host Retina , 2006, Stem cells.

[54]  Shuh Narumiya,et al.  Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell‐derived neural precursors , 2008, Journal of neuroscience research.

[55]  I. Weissman,et al.  Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Lin Xie,et al.  Transplantation of Human Neural Precursor Cells in Matrigel Scaffolding Improves Outcome from Focal Cerebral Ischemia after Delayed Postischemic Treatment in Rats , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[57]  Jeffrey M Karp,et al.  Mesenchymal stem cell homing: the devil is in the details. , 2009, Cell stem cell.