Endogenous electric fields as guiding cue for cell migration

This review covers two topics: (1) “membrane potential of low magnitude and related electric fields (bioelectricity)” and (2) “cell migration under the guiding cue of electric fields (EF).”Membrane potentials for this “bioelectricity” arise from the segregation of charges by special molecular machines (pumps, transporters, ion channels) situated within the plasma membrane of each cell type (including eukaryotic non-neural animal cells). The arising patterns of ion gradients direct many cell- and molecular biological processes such as embryogenesis, wound healing, regeneration. Furthermore, EF are important as guiding cues for cell migration and are often overriding chemical or topographic cues. In osteoblasts, for instance, the directional information of EF is captured by charged transporters on the cell membrane and transferred into signaling mechanisms that modulate the cytoskeleton and motor proteins. This results in a persistent directional migration along an EF guiding cue. As an outlook, we discuss questions concerning the fluctuation of EF and the frequencies and mapping of the “electric” interior of the cell. Another exciting topic for further research is the modeling of field concepts for such distant, non-chemical cellular interactions.

[1]  C. Akerman,et al.  A genetically-encoded chloride and pH sensor for dissociating ion dynamics in the nervous system , 2013, Front. Cell. Neurosci..

[2]  A. Mogilner,et al.  Different Roles of Membrane Potentials in Electrotaxis and Chemotaxis of Dictyostelium Cells , 2011, Eukaryotic Cell.

[3]  M. Mercola,et al.  Asymmetries in H+/K+-ATPase and Cell Membrane Potentials Comprise a Very Early Step in Left-Right Patterning , 2002, Cell.

[4]  Dany S. Adams,et al.  Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates , 2006, Development.

[5]  M. Landthaler,et al.  Luminescent Dual Sensors Reveal Extracellular pH-Gradients and Hypoxia on Chronic Wounds That Disrupt Epidermal Repair , 2014, Theranostics.

[6]  Bing Song,et al.  NHE3 phosphorylation via PKCη marks the polarity and orientation of directionally migrating cells , 2014, Cellular and Molecular Life Sciences.

[7]  R. Shi,et al.  Endogenous ionic currents and voltages in amphibian embryos , 1994 .

[8]  A. Loof All animals develop from a blastula: consequences of an undervalued definition for thinking on development. , 1992 .

[9]  M. Zernicka-Goetz Faculty Opinions recommendation of Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning. , 2002 .

[10]  C. McCaig,et al.  Physiological electrical fields modify cell behaviour. , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  M. Levin,et al.  Serotonin Signaling Is a Very Early Step in Patterning of the Left-Right Axis in Chick and Frog Embryos , 2005, Current Biology.

[12]  Eugene Berezikov,et al.  The Flatworm Macrostomum lignano Is a Powerful Model Organism for Ion Channel and Stem Cell Research , 2012, Stem cells international.

[13]  Richard Nuccitelli,et al.  A computerized 2-dimensional vibrating probe for mapping extracellular current patterns , 1992, Journal of Neuroscience Methods.

[14]  K R Robinson,et al.  The responses of cells to electrical fields: a review , 1985, The Journal of cell biology.

[15]  F. D. Houghton,et al.  Role of gap junctions during early embryo development. , 2005, Reproduction.

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

[17]  H. Petty,et al.  Ion channel clustering enhances weak electric field detection by neutrophils: apparent roles of SKF96365-sensitive cation channels and myeloperoxidase trafficking in cellular responses , 2005, European Biophysics Journal.

[18]  Christof Niehrs,et al.  On growth and form: a Cartesian coordinate system of Wnt and BMP signaling specifies bilaterian body axes , 2010, Development.

[19]  J. Ralphs,et al.  Tendon cells in vivo form a three dimensional network of cell processes linked by gap junctions. , 1996, Journal of anatomy.

[20]  M. Levin,et al.  Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation , 2012, Cell and Tissue Research.

[21]  Y. Schiffmann Symmetry breaking and convergent extension in early chordate development. , 2006, Progress in biophysics and molecular biology.

[22]  R. Borgens Are limb development and limb regeneration both initiated by an integumentary wounding? A hypothesis. , 1984, Differentiation; research in biological diversity.

[23]  A. M. Turing,et al.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[24]  Michael Levin,et al.  Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning , 2012, Biosyst..

[25]  Paul G. McMenamin,et al.  Cutting Edge: Membrane Nanotubes In Vivo: A Feature of MHC Class II+ Cells in the Mouse Cornea1 , 2008, The Journal of Immunology.

[26]  S. Kortagere,et al.  Histone deacetylase activity is necessary for left-right patterning during vertebrate development , 2011, BMC Developmental Biology.

[27]  Michael Levin,et al.  The wisdom of the body: future techniques and approaches to morphogenetic fields in regenerative medicine, developmental biology and cancer. , 2011, Regenerative medicine.

[28]  R. Blakely,et al.  Serotonin Transporter Function Is an Early Step in Left-Right Patterning in Chick and Frog Embryos , 2005, Developmental Neuroscience.

[29]  Dany S. Adams,et al.  H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration , 2007, Development.

[30]  Nickolay V. Bukoreshtliev,et al.  Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels , 2010, Proceedings of the National Academy of Sciences.

[31]  N. Özkucur,et al.  Persistent directional cell migration requires ion transport proteins as direction sensors and membrane potential differences in order to maintain directedness , 2011, BMC Cell Biology.

[32]  W. Scott,et al.  Endogenous electric current is associated with normal development of the vertebrate limb , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[33]  L. Schoofs,et al.  The Fading Electricity Theory of Ageing: The missing biophysical principle? , 2013, Ageing Research Reviews.

[34]  Michael Levin,et al.  Large-scale biophysics: ion flows and regeneration. , 2007, Trends in cell biology.

[35]  R. Shi,et al.  Three‐dimensional gradients of voltage during development of the nervous system as invisible coordinates for the establishment of embryonic pattern , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  M. Levin,et al.  Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model , 2013, Disease Models & Mechanisms.

[37]  F. Franciolini,et al.  Evolution of ionic channels of biological membranes. , 1989, Molecular biology and evolution.

[38]  A. Loof The electrical dimension of cells: the cell as a miniature electrophoresis chamber. , 1986 .

[39]  H. Gerdes,et al.  Multi-Level Communication of Human Retinal Pigment Epithelial Cells via Tunneling Nanotubes , 2012, PloS one.

[40]  Michael Levin,et al.  Bioelectric signaling regulates head and organ size during planarian regeneration , 2013, Development.

[41]  R. Isseroff,et al.  Human keratinocytes migrate to the negative pole in direct current electric fields comparable to those measured in mammalian wounds. , 1996, Journal of cell science.

[42]  R. Funk Ion Gradients in Tissue and Organ Biology , 2013 .

[43]  N. Özkucur,et al.  Ion imaging during axolotl tail regeneration in vivo , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[44]  M. Wheatly,et al.  Molecular biology of ion motive proteins in comparative models , 2004, Journal of Experimental Biology.

[45]  K. Hotary,et al.  Evidence of a role for endogenous electrical fields in chick embryo development. , 1992, Development.

[46]  Richard Nuccitelli,et al.  AN ULTRASENSITIVE VIBRATING PROBE FOR MEASURING STEADY EXTRACELLULAR CURRENTS , 1974, The Journal of cell biology.

[47]  A. Albertengo [Skin flaps]. , 1953, Anales de cirugia.

[48]  Takashi Gojobori,et al.  Long-range neural and gap junction protein-mediated cues control polarity during planarian regeneration. , 2010, Developmental biology.

[49]  R. Binggeli,et al.  Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions. , 1986, Journal of theoretical biology.

[50]  Z. Madeja,et al.  Directional movement of rat prostate cancer cells in direct-current electric field: involvement of voltagegated Na+ channel activity. , 2001, Journal of cell science.

[51]  Y. Kariya,et al.  beta4 integrin and epidermal growth factor coordinately regulate electric field-mediated directional migration via Rac1. , 2006, Molecular biology of the cell.

[52]  Min Zhao,et al.  Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN , 2006, Nature.

[53]  M. Levin Regeneration: Recent advances, major puzzles, and biomedical opportunities. , 2009, Seminars in cell & developmental biology.

[54]  E. S. Goodrich,et al.  The science and philosophy of the organism , 1929, Archiv für Entwicklungsmechanik der Organismen.

[55]  J. Culotti,et al.  Netrins and Wnts Function Redundantly to Regulate Antero-Posterior and Dorso-Ventral Guidance in C. elegans , 2014, PLoS genetics.

[56]  Michael Levin,et al.  Induction of Vertebrate Regeneration by a Transient Sodium Current , 2010, The Journal of Neuroscience.

[57]  C. McCaig,et al.  Electrical dimensions in cell science , 2009, Journal of Cell Science.

[58]  Laura N. Vandenberg,et al.  Polarity proteins are required for left–right axis orientation and twin–twin instruction , 2012, Genesis.

[59]  Raoul Kopelman,et al.  "Nanosized voltmeter" enables cellular-wide electric field mapping. , 2007, Biophysical journal.

[60]  Yong-Eun Koo Lee,et al.  Nanoparticle PEBBLE sensors in live cells. , 2012, Methods in enzymology.

[61]  J. Forrester,et al.  Human corneal epithelial cells reorient and migrate cathodally in a small applied electric field. , 1997, Current eye research.

[62]  R. Isseroff,et al.  Electrical stimulation of wound healing. , 2003, The Journal of investigative dermatology.

[63]  Michael Levin,et al.  Normalized shape and location of perturbed craniofacial structures in the Xenopus tadpole reveal an innate ability to achieve correct morphology , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[64]  S. H. Young,et al.  Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca²+ oscillations in pancreatic cancer PANC-1 cells. , 2010, Biochemical and biophysical research communications.

[65]  J. Forrester,et al.  Nerve regeneration and wound healing are stimulated and directed by an endogenous electrical field in vivo , 2004, Journal of Cell Science.

[66]  N. Özkucur,et al.  Phospho-NHE3 forms membrane patches and interacts with beta-actin to sense and maintain constant direction during cell migration. , 2014, Experimental cell research.

[67]  Paul E. Lammert,et al.  ION DRIVE FOR VESICLES AND CELLS , 1996 .

[68]  A. Mogilner,et al.  Keratocyte Fragments and Cells Utilize Competing Pathways to Move in Opposite Directions in an Electric Field , 2013, Current Biology.

[69]  R. Borgens,et al.  Skin flaps inhibit both the current of injury at the amputation surface and regeneration of that limb in newts. , 2002, The Journal of experimental zoology.

[70]  Richard Nuccitelli,et al.  A role for endogenous electric fields in wound healing. , 2003, Current topics in developmental biology.

[71]  M. Donowitz,et al.  Regulatory binding partners and complexes of NHE3. , 2007, Physiological reviews.

[72]  Greg M. Allen,et al.  Article Electrophoresis of Cellular Membrane Components Creates the Directional Cue Guiding Keratocyte Galvanotaxis , 2022 .

[73]  C. McCaig,et al.  The role of electrical signals in murine corneal wound re‐epithelialization , 2011, Journal of cellular physiology.

[74]  M. Bastiani,et al.  An electrical block is required to prevent polyspermy in eggs fertilized by natural mating of Xenopus laevis. , 1982, Developmental biology.

[75]  O. Kann,et al.  Neurobiology of Disease Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures Emerging Evidence Suggests That Mitochondrial Dysfunction Contributes to the Pathophysiology of Epilepsy. Recurrent Mitochondrial Ca 2ϩ Ion , 2022 .

[76]  S. Courtneidge,et al.  The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function , 2011, Nature Reviews Molecular Cell Biology.

[77]  Albrecht Schwab,et al.  Intracellular pH gradients in migrating cells. , 2011, American journal of physiology. Cell physiology.

[78]  B. Reid,et al.  Non-invasive measurement of bioelectric currents with a vibrating probe , 2007, Nature Protocols.

[79]  M. Levin Bioelectric mechanisms in regeneration: Unique aspects and future perspectives. , 2009, Seminars in cell & developmental biology.

[80]  Min Zhao,et al.  Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. , 2006, Nature.

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

[82]  Michael Levin,et al.  Endogenous bioelectrical networks store non‐genetic patterning information during development and regeneration , 2014, The Journal of physiology.

[83]  Michael Levin,et al.  Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration. , 2005, Developmental biology.

[84]  M. Iselin [ON NERVE REGENERATION]. , 1964, Memoires. Academie de chirurgie.

[85]  Nurdan Özkucur,et al.  Local Calcium Elevation and Cell Elongation Initiate Guided Motility in Electrically Stimulated Osteoblast-Like Cells , 2009, PloS one.

[86]  A. Mogilner,et al.  Airway epithelial wounds in rhesus monkey generate ionic currents that guide cell migration to promote healing. , 2011, Journal of applied physiology.

[87]  A. De Loof The electrical dimension of cells: the cell as a miniature electrophoresis chamber. , 1986, International review of cytology.

[88]  Giancarlo Succi,et al.  Non-invasive Measurement , 2014 .

[89]  K. Hotary,et al.  Endogenous electrical currents and the resultant voltage gradients in the chick embryo. , 1990, Developmental biology.

[90]  Hans-Hermann Gerdes,et al.  Developing Neurons Form Transient Nanotubes Facilitating Electrical Coupling and Calcium Signaling with Distant Astrocytes , 2012, PloS one.

[91]  W F Boron,et al.  Intracellular pH. , 1981, Physiological reviews.

[92]  Min Zhao,et al.  Electrical cues regulate the orientation and frequency of cell division and the rate of wound healing in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[93]  Y. Schiffmann The Turing-Child energy field as a driver of early mammalian development. , 2008, Progress in biophysics and molecular biology.

[94]  Richard H W Funk,et al.  Electromagnetic effects - From cell biology to medicine. , 2009, Progress in histochemistry and cytochemistry.

[95]  R B Borgens,et al.  Bioelectricity and regeneration: large currents leave the stumps of regenerating newt limbs. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[96]  A. Pereda,et al.  Electrical synapses and their functional interactions with chemical synapses , 2014, Nature Reviews Neuroscience.

[97]  H. Petty,et al.  Real-time control of neutrophil metabolism by very weak ultra-low frequency pulsed magnetic fields. , 2005, Biophysical journal.