Abstract
Biophysical signaling, an integral regulator of long-term cell behavior in both excitable and non-excitable cell types, offers enormous potential for modulation of important cell functions. Of particular interest to current regenerative medicine efforts, we review several examples that support the functional role of transmembrane potential (Vmem) in the regulation of proliferation and differentiation. Interestingly, distinct Vmem controls are found in many cancer cell and precursor cell systems, which are known for their proliferative and differentiation capacities, respectively. Collectively, the data demonstrate that bioelectric properties can serve as markers for cell characterization and can control cell mitotic activity, cell cycle progression, and differentiation. The ability to control cell functions by modulating bioelectric properties such as Vmem would be an invaluable tool for directing stem cell behavior toward therapeutic goals. Biophysical properties of stem cells have only recently begun to be studied and are thus in need of further characterization. Understanding the molecular and mechanistic basis of biophysical regulation will point the way toward novel ways to rationally direct cell functions, allowing us to capitalize upon the potential of biophysical signaling for regenerative medicine and tissue engineering.
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Robinson, K. R., & Messerli, M. A. (1996). Electric embryos: the embryonic epithelium as a generator of developmental information. In C. D. McCaig (Ed.), Nerve growth and guidance (pp. 131–150). London: Portland.
Jaffe, L. F., & Nuccitelli, R. (1977). Electrical controls of development. Annual Review of Biophysics and Bioengineering, 6, 445–476.
Lund, E. (1947). Bioelectric fields and growth. Austin: University of Texas Press.
Borgens, R. B. (1982). What is the role of naturally produced electric current in vertebrate regeneration and healing. International Review of Cytology, 76, 245–298.
Borgens, R. B., Vanable, J. W., Jr., & Jaffe, L. F. (1977). Bioelectricity and regeneration. I. Initiation of frog limb regeneration by minute currents. Journal of Experimental Zoology, 200, 403–416.
Mathews, A. P. (1903). Electrical polarity in the hydroids. American Journal of Physiology, 8, 294–299.
McCaig, C. D., Rajnicek, A. M., Song, B., & Zhao, M. (2005). Controlling cell behavior electrically: Current views and future potential. Physiological Reviews, 85, 943–978.
Levin, M. (2007). Large-scale biophysics: Ion flows and regeneration. Trends in Cell Biology, 17, 262–271.
Adams, D. S., Masi, A., & Levin, M. (2007). H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration. Development, 134, 1323–1335.
Zhao, M., Song, B., Pu, J., et al. (2006). Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature, 442, 457–460.
Arcangeli, A. (2005). Expression and role of hERG channels in cancer cells. Novartis Foundation Symposium, 266, 225–232. discussion 32–4.
Mycielska, M. E., & Djamgoz, M. B. (2004). Cellular mechanisms of direct-current electric field effects: Galvanotaxis and metastatic disease. Journal of Cell Science, 117, 1631–1639.
Wang, Z. (2004). Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Archiv, 448, 274–286.
Bortner, C. D., & Cidlowski, J. A. (2004). The role of apoptotic volume decrease and ionic homeostasis in the activation and repression of apoptosis. Pflugers Archiv, 448, 313–318.
Franco, R., Bortner, C. D., & Cidlowski, J. A. (2006). Potential roles of electrogenic ion transport and plasma membrane depolarization in apoptosis. Journal of Membrane Biology, 209, 43–58.
Ling, G., & Gerard, R. W. (1949). The normal membrane potential of frog sartorius fibers. Journal of Cellular and Comparative Physiology, 34, 383–396.
Stuart, G. J., & Palmer, L. M. (2006). Imaging membrane potential in dendrites and axons of single neurons. Pflugers Archiv, 453, 403–410.
Molleman, A. (2003). Patch clamping: an introductory guide to patch clamp electrophysiology. Chichester, England: Wiley.
González, J. E., & Tsien, R. Y. (1997). Improved indicators of cell membrane potential that use fluorescence resonance energy transfer. Chemistry & Biology, 4, 269–277.
Loew, L. M. (1992). Voltage-sensitive dyes: Measurement of membrane potentials induced by DC and AC electric fields. Bioelectromagnetics, (Suppl 1):179–89.
Brüggemann, A., Stoelzle, S., George, M., Behrends, J. C., & Fertig, N. (2006). Microchip technology for automated and parallel patch-clamp recording. Small, 2, 840–846.
Millard, A. C., Jin, L., Wei, M. D., Wuskell, J. P., Lewis, A., & Loew, L. M. (2004). Sensitivity of second harmonic generation from styryl dyes to transmembrane potential. Biophysical Journal, 86, 1169–1176.
Plášek, J., & Sigler, K. (1996). Slow fluorescent indicators of membrane potential: A survey of different approaches to probe response analysis. Journal of Photochemistry and Photobiology. B, Biology, 33, 101–124.
Binggeli, R., & Weinstein, R. C. (1986). Membrane potentials and sodium channels: Hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions. Journal of Theoretical Biology, 123, 377–401.
Cone, C. D., Jr. (1971). Unified theory on the basic mechanism of normal mitotic control and oncogenesis. Journal of Theoretical Biology, 30, 151–181.
Cone, C. D., Jr., & Tongier, M., Jr. (1973). Contact inhibition of division: Involvement of the electrical transmembrane potential. Journal of Cellular Physiology, 82, 373–386.
Adams, D. S., & Levin, M. (2006). Strategies and techniques for investigation of biophysical signals in patterning. In M. Whitman & A. K. Sater (Eds.), Analysis of growth factor signaling in embryos: Taylor and Francis books (pp. 177–262).
MacFarlane, S. N., & Sontheimer, H. (2000). Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes. GLIA, 30, 39–48.
Dubois, J. M., & Rouzaire-Dubois, B. (1993). Role of potassium channels in mitogenesis. Progress in Biophysics and Molecular Biology, 59, 1–21.
Wonderlin, W. F., & Strobl, J. S. (1996). Potassium channels, proliferation and G1 progression. Journal of Membrane Biology, 154, 91–107.
Cone, C. D., & Cone, C. M. (1976). Induction of mitosis in mature neurons in central nervous system by sustained depolarization. Science, 192, 155–158.
Stillwell, E. F., Cone, C. M., & Cone, C. D. (1973). Stimulation of DNA synthesis in CNS neurones by sustained depolarisation. Nature: New Biology, 246, 110–111.
Cone, C. D., & Tongier, M. (1971). Control of somatic cell mitosis by simulated changes in the transmembrane potential level. Oncology, 25, 168–182.
Bordey, A., Lyons, S. A., Hablitz, J. J., & Sontheimer, H. (2001). Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia. Journal of Neurophysiology, 85, 1719–1731.
MacFarlane, S. N., & Sontheimer, H. (1997). Electrophysiological changes that accompany reactive gliosis in vitro. Journal of Neuroscience, 17, 7316–7329.
Bordey, A., & Sontheimer, H. (1997). Postnatal development of ionic currents in rat hippocampal astrocytes in situ. Journal of Neurophysiology, 78, 461–477.
Ransom, C. B., & Sontheimer, H. (1995). Biophysical and pharmacological characterization of inwardly rectifying K+ currents in rat spinal cord astrocytes. Journal of Neurophysiology, 73, 333–346.
Owens, G. K., Kumar, M. S., & Wamhoff, B. R. (2004). Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiological Reviews, 84, 767–801.
Beech, D. J. (2007). Ion channel switching and activation in smooth-muscle cells of occlusive vascular diseases. Biochemical Society Transactions, 35, 890–894.
Gollasch, M., Haase, H., Ried, C., et al. (1998). L-type calcium channel expression depends on the differentiated state of vascular smooth muscle cells. FASEB Journal, 12, 593–601.
Richard, S., Neveu, D., Carnac, G., Bodin, P., Travo, P., & Nargeot, J. (1992). Differential expression of voltage-gated Ca2+-currents in cultivated aortic myocytes. Biochimica et Biophysica Acta—Protein Structure and Molecular Enzymology, 1160, 95–104.
Neylon, C. B., Lang, R. J., Fu, Y., Bobik, A., & Reinhart, P. H. (1999). Molecular cloning and characterization of the intermediate-conductance Ca(2+)-activated K(+) channel in vascular smooth muscle: relationship between K(Ca) channel diversity and smooth muscle cell function. Circulation Research, 85, e33–e43.
Freedman, B. D., Price, M. A., & Deutsch, C. J. (1992). Evidence for voltage modulation of IL-2 production in mitogen-stimulated human peripheral blood lymphocytes. Journal of Immunology, 149, 3784–3794.
Lin, C. S., Boltz, R. C., Blake, J. T., et al. (1993). Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. The Journal of Experimental Medicine, 177, 637–645.
Price, M., Lee, S. C., & Deutsch, C. (1989). Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes. Proceedings of the National Academy of Sciences of the United States of America, 86, 10171–10175.
Amigorena, S., Choquet, D., Teillaud, J. L., Korn, H., & Fridman, W. H. (1990). Ion channel blockers inhibit B cell activation at a precise stage of the G1 phase of the cell cycle. Possible involvement of K+ channels. Journal of Immunology, 144, 2038–2045.
Lee, S. C., Sabath, D. E., Deutsch, C., & Prystowsky, M. B. (1986). Increased voltage-gated potassium conductance during interleukin 2-stimulated proliferation of a mouse helper T lymphocyte clone. Journal of Cell Biology, 102, 1200–1208.
Cahalan, M. D., & Chandy, K. G. (1997). Ion channels in the immune system as targets for immunosuppression. Current Opinion in Biotechnology, 8, 749–756.
Deutsch, C., Krause, D., & Lee, S. C. (1986). Voltage-gated potassium conductance in human T-lymphocytes stimulated with phorbol ester. Journal of Physiology, 372, 405–423.
Ghanshani, S., Wulff, H., Miller, M. J., et al. (2000). Up-regulation of the IKCa1 potassium channel during T-cell activation: Molecular mechanism and functional consequences. Journal of Biological Chemistry, 275, 37137–37149.
Grissmer, S., Nguyen, A. N., & Cahalan, M. D. (1993). Calcium-activated potassium channels in resting and activated human T lymphocytes: Expression levels, calcium dependence, ion selectivity, and pharmacology. Journal of General Physiology, 102, 601–630.
Khanna, R., Change, M. C., Joiner, W. J., Kaczmarek, L. K., & Schlichter, L. C. (1999). hSK4/hIK1, a calmodulin-binding K(Ca) channel in human T lymphocytes. Roles in proliferation and volume regulation. Journal of Biological Chemistry, 274, 14838–14849.
Kim, C. F., & Dirks, P. B. (2008). Cancer and stem cell biology: How tightly intertwined? Cell Stem Cell, 3, 147–150.
Normile, D. (2002). Cell proliferation. Common control for cancer, stem cells. Science, 298, 1869.
Wonderlin, W. F., Woodfork, K. A., & Strobl, J. S. (1995). Changes in membrane potential during the progression of MCF-7 human mammary tumor cell through the cell cycle. Journal of Cellular Physiology, 165, 177–185.
Woodfork, K. A., Wonderlin, W. F., Peterson, V. A., & Strobl, J. S. (1995). Inhibition of ATP-sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture. Journal of Cellular Physiology, 162, 163–171.
Klimatcheva, E., & Wonderlin, W. F. (1999). An ATP-sensitive K+ current that regulates progression through early G1 phase of the cell cycle in MCF-7 human breast cancer cells. Journal of Membrane Biology, 171, 35–46.
Ouadid-Ahidouch, H., Chaussade, F., Roudbaraki, M., et al. (2000). Kv1.1 K+ channels identification in human breast carcinoma cells: Involvement in cell proliferation. Biochemical and Biophysical Research Communications, 278, 272–277.
Ouadid-Ahidouch, H., Le Bourhis, X., Roudbaraki, M., Toillon, R. A., Delcourt, P., & Prevarskaya, N. (2001). Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: Possible Involvement of a h-ether.a-gogo K+ channel. Receptors and Channels, 7, 345–356.
Ouadid-Ahidouch, H., Roudbaraki, M., Ahidouch, A., Delcourt, P., & Prevarskaya, N. (2004). Cell-cycle-dependent expression of the large Ca2+-activated K+ channels in breast cancer cells. Biochemical and Biophysical Research Communications, 316, 244–251.
Ouadid-Ahidouch, H., Roudbaraki, M., Delcourt, P., Ahidouch, A., Joury, N., & Prevarskaya, N. (2004). Functional and molecular identification of intermediate-conductance Ca 2+-activated K+ channels in breast cancer cells: Association with cell cycle progression. American Journal of Physiology. Cell Physiology, 287, C125–C134.
Ouadid-Ahidouch, H., & Ahidouch, A. (2008). K+ channel expression in human breast cancer cells: Involvement in cell cycle regulation and carcinogenesis. Journal of Membrane Biology, 221, 1–6.
MacFarlane, S. N., & Sontheimer, H. (2000). Modulation of Kv1.5 currents by Src tyrosine phosphorylation: Potential role in the differentiation of astrocytes. Journal of Neuroscience, 20, 5245–5253.
Sontheimer, H. (1994). Voltage-dependent ion channels in glial cells. GLIA, 11, 156–172.
Li, L., Head, V., & Timpe, L. C. (2001). Identification of an inward rectifier potassium channel gene expressed in mouse cortical astrocytes. GLIA, 33, 57–71.
Higashimori, H., & Sontheimer, H. (2007). Role of Kir4.1 channels in growth control of glia. GLIA, 55, 1668–1679.
Yasuda, T., Bartlett, P. F., & Adams, D. J. (2008). Kir and Kv channels regulate electrical properties and proliferation of adult neural precursor cells. Molecular and Cellular Neurosciences, 37, 284–297.
Wang, K., Xue, T., Tsang, S. Y., et al. (2005). Electrophysiological properties of pluripotent human and mouse embryonic stem cells. Stem Cells, 23, 1526–1534.
Morokuma, J., Blackiston, D., Adams, D. S., Seebohm, G., Trimmer, B., & Levin, M. (2008). Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 16608–16613.
Ferletta, M., Uhrbom, L., Olofsson, T., Ponten, F., & Westermark, B. (2007). Sox10 has a broad expression pattern in gliomas and enhances platelet-derived growth factor-B-induced gliomagenesis. Molecular Cancer Research, 5, 891–897.
Bannykh, S. I., Stolt, C. C., Kim, J., Perry, A., & Wegner, M. (2006). Oligodendroglial-specific transcriptional factor SOX10 is ubiquitously expressed in human gliomas. Journal of Neuro-oncology, 76, 115–127.
Martin, T. A., Goyal, A., Watkins, G., & Jiang, W. G. (2005). Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Annals of Surgical Oncology, 12, 488–496.
Kurrey, N. K., Amit, K., & Bapat, S. A. (2005). Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecologic Oncology, 97, 155–165.
Adams, D. S., Masi, A., & Levin, M. (2007). H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration. Development, 134, 1323–1335.
Miller, J. P., Yeh, N., Vidal, A., & Koff, A. (2007). Interweaving the cell cycle machinery with cell differentiation. Cell Cycle, 6, 2932–2938.
Arcangeli, A., Bianchi, L., Becchetti, A., et al. (1995). A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammalian neuroblastoma cells. Journal of Physiology, 489, 455–471.
Arcangeli, A., Rosati, B., Cherubini, A., et al. (1998). Long term exposure to retinoic acid induces the expression of IRK1 channels in HERG channel-endowed neuroblastoma cells. Biochemical and Biophysical Research Communications, 244, 706–711.
Arcangeli, A., Rosati, B., Cherubini, A., et al. (1997). HERG- and IRK-like inward rectifier currents are sequentially expressed during neuronal development of neural crest cells and their derivatives. European Journal of Neuroscience, 9, 2596–2604.
Arcangeli, A., Rosati, B., Crociani, O., et al. (1999). Modulation of HERG current and herg gene expression during retinoic acid treatment of human neuroblastoma cells: Potentiating effects of BDNF. Journal of Neurobiology, 40, 214–225.
Biagiotti, T., D’Amico, M., Marzi, I., et al. (2006). Cell renewing in neuroblastoma: Electrophysiological and immunocytochemical characterization of stem cells and derivatives. Stem Cells, 24, 443–453.
Sun, W., Buzanska, L., Domanska-Janik, K., Salvi, R. J., & Stachowiak, M. K. (2005). Voltage-sensitive and ligand-gated channels in differentiating neural stem-like cells derived from the nonhematopoietic fraction of human umbilical cord blood. Stem Cells, 23, 931–945.
Cho, T., Bae, J. H., Choi, H. B., et al. (2002). Human neural stem cells: Electrophysiological properties of voltage-gated ion channels. NeuroReport, 13, 1447–1452.
Chafai, M., Louiset, E., Basille, M., et al. (2006). PACAP and VIP promote initiation of electrophysiological activity in differentiating embryonic stem cells. Annals of the New York Academy of Sciences, 1070, 185–189.
Van Kempen, M. J. A., Van Ginneken, A., De Grijs, I., et al. (2003). Expression of the electrophysiological system during murine embryonic stem cell cardiac differentiation. Cellular Physiology and Biochemistry, 13, 263–270.
Van Der Heyden, M. A. G., Van Kempen, M. J. A., Tsuji, Y., Rook, M. B., Jongsma, H. J., & Opthof, T. (2003). P19 embryonal carcinoma cells: A suitable model system for cardiac electrophysiological differentiation at the molecular and functional level. Cardiovascular Research, 58, 410–422.
Fioretti, B., Pietrangelo, T., Catacuzzeno, L., & Franciolini, F. (2005). Intermediate-conductance Ca2+-activated K+ channel is expressed in C2C12 myoblasts and is downregulated during myogenesis. American Journal of Physiology. Cell Physiology, 289, C89–C96.
Kubo, Y. (1991). Comparison of initial stages of muscle differentiation in rat and mouse myoblastic and mouse mesodermal stem cell lines. Journal of Physiology, 442, 743–759.
Voets, T., Wei, L., De Smet, P., et al. (1997). Downregulation of volume-activated Cl- currents during muscle differentiation. American Journal of Physiology. Cell Physiology, 272, C667–C674.
Lesage, F., Attali, B., Lazdunski, M., & Barhanin, J. (1992). Developmental expression of voltage-sensitive K+ channels in mouse skeletal muscle and C2C12 cells. FEBS Letters, 310, 162–166.
Wieland, S. J., & Gong, Q. H. (1995). Modulation of a potassium conductance in developing skeletal muscle. American Journal of Physiology. Cell Physiology, 268, C490–C495.
Hamann, M., Widmer, H., Baroffio, A., et al. (1994). Sodium and potassium currents in freshly isolated and in proliferating human muscle satellite cells. Journal of Physiology, 475, 305–317.
Bernheim, L., Liu, J. H., Hamann, M., Haenggeli, C. A., Fischer-Lougheed, J., & Bader, C. R. (1996). Contribution of a non-inactivating potassium current to the resting membrane potential of fusion-competent human myoblasts. Journal of Physiology, 493, 129–141.
Bijlenga, P., Liu, J. H., Espinos, E., et al. (2000). T-type α1H Ca2+ channels are involved in Ca2+ signaling during terminal differentiation (fusion) of human myoblasts. Proceedings of the National Academy of Sciences of the United States of America, 97, 7627–7632.
Bijlenga, P., Occhiodoro, T., Liu, J. H., Bader, C. R., Bernheim, L., & Fischer-Lougheed, J. (1998). An ether-a-go-go K+ current, I(h-eag), contributes to the hyperpolarization of human fusion-competent myoblasts. Journal of Physiology, 512, 317–323.
Fischer-Lougheed, J., Liu, J. H., Espinos, E., et al. (2001). Human myoblast fusion requires expression of functional inward rectifier Kir2.1 channels. Journal of Cell Biology, 153, 677–685.
Liu, J. H., Bijlenga, P., Fischer-Lougheed, J., et al. (1998). Role of an inward rectifier K+ current and of hyperpolarization in human myoblast fusion. Journal of Physiology, 510, 467–476.
Messenger, E. A., & Warner, A. E. (1979). The function of the sodium pump during differentiation of amphibian embryonic neurones. Journal of Physiology, 292, 85–105.
Messenger, E. A., & Warner, A. E. (1976). The effect of inhibiting the sodium pump on the differentiation of nerve cells [proceedings]. Journal of Physiology, 263, 211P–212P.
Konig, S., Hinard, V., Arnaudeau, S., et al. (2004). Membrane hyperpolarization triggers myogenin and myocyte enhancer factor-2 expression during human myoblast differentiation. Journal of Biological Chemistry, 279, 28187–28196.
Hinard, V., Belin, D., Konig, S., Bader, C. R., & Bernheim, L. (2008). Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242. Development, 135, 859–867.
Konig, S., Béguet, A., Bader, C. R., & Bernheim, L. (2006). The calcineurin pathway links hyperpolarization (Kir2.1)-induced Ca2+ signals to human myoblast differentiation and fusion. Development, 133, 3107–3114.
Yin, Z., Tong, Y., Zhu, H., & Watsky, M. A. (2008). ClC-3 is required for LPA-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. American Journal of Physiology. Cell Physiology, 294, C535–C542.
Shirihai, O., Attali, B., Dagan, D., & Merchav, S. (1998). Expression of two inward rectifier potassium channels is essential for differentiation of primitive human hematopoietic progenitor cells. Journal of Cellular Physiology, 177, 197–205.
Shirihai, O., Merchav, S., Attali, B., & Dagan, D. (1996). K+ channel antisense oligodeoxynucleotides inhibit cytokine-induced expansion of human hemopoietic progenitors. Pflugers Archiv, 431, 632–638.
Nakanishi, S., & Okazawa, M. (2006). Membrane potential-regulated Ca2+ signalling in development and maturation of mammalian cerebellar granule cells. Journal of Physiology, 575, 389–395.
Rossi, P., D’Angelo, E., Magistretti, J., Toselli, M., & Taglietti, V. (1994). Age dependent expression of high-voltage activated calcium currents during cerebellar granule cell development in situ. Pflugers Archiv, 429, 107–116.
Sato, M., Suzuki, K., Yamazaki, H., & Nakanishi, S. (2005). A pivotal role of calcineurin signaling in development and maturation of postnatal cerebellar granule cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 5874–5879.
Sundelacruz, S., Levin, M., & Kaplan, D. L. (2008). Membrane potential controls adipogenic and osteogenic differentiation of mesenchymal stem cells. PLoS ONE, 3, e3737.
Echeverri, K., & Tanaka, E. M. (2002). Mechanisms of muscle dedifferentiation during regeneration. Seminars in Cell & Developmental Biology, 13, 353–360.
Odelberg, S. J. (2002). Inducing cellular dedifferentiation: A potential method for enhancing endogenous regeneration in mammals. Seminars in Cell & Developmental Biology, 13, 335–343.
Chiabrera, A., Hinsenkamp, M., Pilla, A. A., et al. (1979). Cytofluorometry of electromagnetically controlled cell dedifferentiation. Journal of Histochemistry and Cytochemistry, 27, 375–381.
Chiabrera, A., Viviani, R., Parodi, G., et al. (1980). Automated absorption image cytometry of electromagnetically exposed frog erythrocytes. Cytometry, 1, 42–48.
Harrington, D. B. (1972). Electrical stimulation of RNA and protein-synthesis in frog erythrocyte. Anatomical Record, 172, 325.
Harrington, D. B., & Becker, R. O. (1973). Electrical stimulation of RNA and protein synthesis in the frog erythrocyte. Experimental Cell Research, 76, 95–98.
Hinsenkamp, M., Chiabrera, A., Ryaby, J., Pilla, A. A., & Bassett, C. A. (1978). Cell behaviour and DNA modification in pulsing electromagnetic fields. Acta Orthopaedica Belgica, 44, 636–650.
Balana, B., Nicoletti, C., Zahanich, I., et al. (2006). 5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells. Cell Research, 16, 949–960.
Ravens, U. (2006). Electrophysiological properties of stem cells. Herz, 31, 123–126.
Wenisch, S., Trinkaus, K., Hild, A., et al. (2006). Immunochemical, ultrastructural and electrophysiological investigations of bone-derived stem cells in the course of neuronal differentiation. Bone, 38, 911–921.
Biagiotti, T., D’Amico, M., Marzi, I., et al. (2006). Cell renewing in neuroblastoma: electrophysiological and immunocytochemical characterization of stem cells and derivatives. Stem Cells, 24, 443–453.
Wang, K., Xue, T., Tsang, S. Y., et al. (2005). Electrophysiological properties of pluripotent human and mouse embryonic stem cells. Stem Cells, 23, 1526–1534.
Flanagan, L. A., Lu, J., Wang, L., et al. (2007). Unique dielectric properties distinguish stem cells and their differentiated progeny. Stem Cells.
Gersdorff Korsgaard, M. P., Christophersen, P., Ahring, P. K., & Olesen, S. P. (2001). Identification of a novel voltage-gated Na+ channel rNa(v)1.5a in the rat hippocampal progenitor stem cell line HiB5. Pflugers Archiv, 443, 18–30.
Heubach, J. F., Graf, E. M., Leutheuser, J., et al. (2004). Electrophysiological properties of human mesenchymal stem cells. Journal of Physiology, 554, 659–672.
Li, G. R., Sun, H., Deng, X., & Lau, C. P. (2005). Characterization of ionic currents in human mesenchymal stem cells from bone marrow. Stem Cells, 23, 371–382.
Bai, X., Ma, J., Pan, Z., et al. (2007). Electrophysiological properties of human adipose tissue-derived stem cells. American Journal of Physiology. Cell Physiology, 293(5), C1539–C1550.
Cai, J., Cheng, A., Luo, Y., et al. (2004). Membrane properties of rat embryonic multipotent neural stem cells. Journal of Neurochemistry, 88, 212–226.
Park, K. S., Jung, K. H., Kim, S. H., et al. (2007). Functional expression of ion channels in mesenchymal stem cells derived from umbilical cord vein. Stem Cells, 25, 2044–2052.
Yu, K., Ruan, D. Y., & Ge, S. Y. (2002). Three electrophysiological phenotypes of cultured human umbilical vein endothelial cells. General Physiology and Biophysics, 21, 315–326.
Baksh, D., Song, L., & Tuan, R. S. (2004). Adult mesenchymal stem cells: Characterization, differentiation, and application in cell and gene therapy. Journal of Cellular and Molecular Medicine, 8, 301–316.
Levin, M. (2007). Large-scale biophysics: Ion flows and regeneration. Trends in Cell Biology, 17, 261–270.
Constantinescu, S. N. (2000). Stem cell generation and choice of fate: Role of cytokines and cellular microenvironment. Journal of Cellular and Molecular Medicine, 4, 233–248.
Bianchi, G., Muraglia, A., Daga, A., Corte, G., Cancedda, R., & Quarto, R. (2001). Microenvironment and stem properties of bone marrow-derived mesenchymal cells. Wound Repair Regen, 9, 460–466.
Kasemeier-Kulesa, J. C., Teddy, J. M., Postovit, L. M., et al. (2008). Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment. Developmental Dynamics, 237, 2657–2666.
Heese, O., Disko, A., Zirkel, D., Westphal, M., & Lamszus, K. (2005). Neural stem cell migration toward gliomas in vitro. Neuro-oncology, 7, 476–484.
Jeon, J. Y., An, J. H., Kim, S. U., Park, H. G., & Lee, M. A. (2008). Migration of human neural stem cells toward an intracranial glioma. Experimental & Molecular Medicine, 40, 84–91.
Quesenberry, P. J., & Becker, P. S. (1998). Stem cell homing: Rolling, crawling, and nesting. Proceedings of the National Academy of Sciences of the United States of America, 95, 15155–15157.
Whetton, A. D., & Graham, G. J. (1999). Homing and mobilization in the stem cell niche. Trends in Cell Biology, 9, 233–238.
Krause, D. S., Theise, N. D., Collector, M. I., et al. (2001). Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105, 369–377.
Penn, M. S., Zhang, M., Deglurkar, I., & Topol, E. J. (2004). Role of stem cell homing in myocardial regeneration. International Journal of Cardiology, 95(Suppl 1), S23–S25.
Chute, J. P. (2006). Stem cell homing. Current Opinion in Hematology, 13, 399–406.
Sanchez Alvarado, A. (2004). Planarians. Current Biology, 14, R737–R738.
Reddien, P. W., & Sanchez Alvarado, A. (2004). Fundamentals of planarian regeneration. Annual Review of Cell and Developmental Biology, 20, 725–757.
Oviedo, N., & Levin, M. (2008). The planarian regeneration model as a context for the study of drug effects and mechanisms. In R. B. Raffa & S. M. Rawls (Eds.), Planaria: A model for drug action and abuse. Austin: RG Landes Co.
Sanchez Alvarado, A. (2003). The freshwater planarian Schmidtea mediterranea: Embryogenesis, stem cells and regeneration. Current Opinion in Genetics and Development, 13, 438–444.
Salo, E., & Baguna, J. (1985). Cell movement in intact and regenerating planarians. Quantitation using chromosomal, nuclear and cytoplasmic markers. Journal of Embryology and Experimental Morphology, 89, 57–70.
Oviedo, N. J., Pearson, B. J., Levin, M., & Sanchez Alvarado, A. (2008). Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling. Disease Models & Mechanisms, 1, 131–143.
Nogi, T., & Levin, M. (2005). Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration. Developmental Biology, 287, 314–335.
Oviedo, N. J., & Levin, M. (2007). smedinx-11 is a planarian stem cell gap junction gene required for regeneration and homeostasis. Development, 134, 3121–3131.
Wong, R. C., Pera, M. F., & Pebay, A. (2008). Role of gap junctions in embryonic and somatic stem cells. Stem Cell Reviews, 4, 283–292.
Spray, D., Harris, A., & Bennett, M. (1981). Equilibrium properties of a voltage-dependent junctional conductance. Journal of General Physiology, 77, 77–93.
Harris, A., Spray, D., & Bennett, M. (1983). Control of intercellular communication by voltage dependence of gap junctional conductance. Journal of Neuroscience, 3, 79–100.
Menichella, D. M., Majdan, M., Awatramani, R., et al. (2006). Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. Journal of Neuroscience, 26, 10984–10991.
Verselis, V., Trexler, E., Bargiello, T., & Bennett, M. (1997). Studies of voltage gating of gap junctions and hemichannels formed by connexin proteins. In R. Latorre, J. Saez (Eds.), From ion channels to cell-to-cell conversations (pp. 323–347). New York.
Morokuma, J., Blackiston, D., Adams, D. S., Seebohm, G., Trimmer, B., & Levin, M. (2008). Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 16608–16613.
Djamgoz, M. B. A., Mycielska, M., Madeja, Z., Fraser, S. P., & Korohoda, W. (2001). Directional movement of rat prostate cancer cells in direct-current electric field: Involvement of voltage-gated Na+ channel activity. Journal of Cell Science, 114, 2697–2705.
Brackenbury, W. J., & Djamgoz, M. B. (2006). Activity-dependent regulation of voltage-gated Na+ channel expression in Mat-LyLu rat prostate cancer cell line. Journal of Physiology, 573, 343–356.
Gruler, H., & Nuccitelli, R. (1991). Neural crest cell galvanotaxis: new data and a novel approach to the analysis of both galvanotaxis and chemotaxis. Cell Motility and the Cytoskeleton, 19, 121–133.
Nuccitelli, R., & Erickson, C. A. (1983). Embryonic cell motility can be guided by physiological electric fields. Experimental Cell Research, 147, 195–201.
Nuccitelli, R., & Smart, T. (1989). Extracellular calcium levels strongly influence neural crest cell galvanotaxis. Biological Bulletin, 176, 130–135.
Adams, D. S., Robinson, K. R., Fukumoto, T., et al. (2006). Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. Development, 133, 1657–1671.
Denker, S. P., & Barber, D. L. (2002). Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. Journal of Cell Biology, 159, 1087–1096.
Levin, M., Buznikov, G. A., & Lauder, J. M. (2006). Of minds and embryos: Left-right asymmetry and the serotonergic controls of pre-neural morphogenesis. Developmental Neuroscience, 28, 171–185.
Shi, H., Halvorsen, Y. D., Ellis, P. N., Wilkison, W. O., & Zemel, M. B. (2000). Role of intracellular calcium in human adipocyte differentiation. Physiological Genomics, 2000, 75–82.
Zayzafoon, M. (2006). Calcium/calmodulin signaling controls osteoblast growth and differentiation. Journal of Cellular Biochemistry, 97, 56–70.
Munaron, L., Antoniotti, S., & Lovisolo, D. (2004). Intracellular calcium signals and control of cell proliferation: How many mechanisms? Journal of Cellular and Molecular Medicine, 8, 161–168.
Whitaker, M. (2006). Calcium microdomains and cell cycle control. Cell Calcium, 40, 585–592.
Soliman, E. M., Rodrigues, M. A., Gomes, D. A., et al. (2009). Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression. Cell Calcium, 45, 284–292.
Palma, V., Kukuljan, M., & Mayor, R. (2001). Calcium mediates dorsoventral patterning of mesoderm in Xenopus. Current Biology, 11, 1606–1610.
Sun, S., Liu, Y., Lipsky, S., & Cho, M. (2007). Physical manipulation of calcium oscillations facilitates osteodifferentiation of human mesenchymal stem cells. FASEB Journal, 21, 1472–1480.
Trollinger, D. R., Isseroff, R. R., & Nuccitelli, R. (2002). Calcium channel blockers inhibit galvanotaxis in human keratinocytes. Journal of Cellular Physiology, 193, 1–9.
Albrieux, M., & Villaz, M. (2000). Bilateral asymmetry of the inositol trisphosphate-mediated calcium signaling in two-cell ascidian embryos. Biology of the Cell, 92, 277–284.
Linask, K. K., Han, M. D., Artman, M., & Ludwig, C. A. (2001). Sodium-calcium exchanger (NCX-1) and calcium modulation: NCX protein expression patterns and regulation of early heart development. Developmental Dynamics, 221, 249–264.
McGrath, J., Somlo, S., Makova, S., Tian, X., & Brueckner, M. (2003). Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell, 114, 61–73.
Raya, A., Kawakami, Y., Rodriguez-Esteban, C., et al. (2004). Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature, 427, 121–128.
Schneider, I., Houston, D. W., Rebagliati, M. R., & Slusarski, D. C. (2007). Calcium fluxes in dorsal forerunner cells antagonize {beta}-catenin and alter left-right patterning. Development.
Slusarski, D. C., & Pelegri, F. (2007). Calcium signaling in vertebrate embryonic patterning and morphogenesis. Developmental Biology, 307, 1–13.
Webb, S. E., & Miller, A. L. (2000). Calcium signalling during zebrafish embryonic development. Bioessays, 22, 113–123.
Jaffe, L. F. (1999). Organization of early development by calcium patterns. Bioessays, 21, 657–667.
Jaffe, L. (1995). Calcium waves and development. In Calcium waves, gradients and oscillations (pp. 4–17). Chichester: CIBA Foundation.
Konig, S., Beguet, A., Bader, C. R., & Bernheim, L. (2006). The calcineurin pathway links hyperpolarization (Kir2.1)-induced Ca2+ signals to human myoblast differentiation and fusion. Development, 133, 3107–3114.
Nilius, B., Schwarz, G., & Droogmans, G. (1993). Control of intracellular calcium by membrane potential in human melanoma cells. American Journal of Physiology, 265, C1501–C1510.
Nilius, B., & Wohlrab, W. (1992). Potassium channels and regulation of proliferation of human melanoma cells. Journal of Physiology, 445, 537–548.
Sasaki, M., Gonzalez-Zulueta, M., Huang, H., et al. (2000). Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America, 97, 8617–8622.
Bidaud, I., Mezghrani, A., Swayne, L. A., Monteil, A., & Lory, P. (2006). Voltage-gated calcium channels in genetic diseases. Biochimica et Biophysica Acta, 1763, 1169–1174.
Cherubini, A., Hofmann, G., Pillozzi, S., et al. (2005). Human ether-a-go-go-related gene 1 channels are physically linked to beta1 integrins and modulate adhesion-dependent signaling. Molecular Biology of the Cell, 16, 2972–2983.
Arcangeli, A., & Becchetti, A. (2006). Complex functional interaction between integrin receptors and ion channels. Trends in Cell Biology, 16, 631–639.
Liu, J., DeYoung, S. M., Zhang, M., Cheng, A., & Saltiel, A. R. (2005). Changes in integrin expression during adipocyte differentiation. Cell Metabolism, 2, 165–177.
Meyers, V. E., Zayzafoon, M., Gonda, S. R., Gathings, W. E., & McDonald, J. M. (2004). Modeled microgravity disrupts collagen I/integrin signaling during osteoblastic differentiation of human mesenchymal stem cells. Journal of Cellular Biochemistry, 93, 697–707.
Nesti, L. J., Caterson, E. J., Wang, M., et al. (2002). TGF-β1 calcium signaling increases α5 integrin expression in osteoblasts. Journal of Orthopaedic Research, 20, 1042–1049.
Iwasaki, H., Murata, Y., Kim, Y., et al. (2008). A voltage-sensing phosphatase, Ci-VSP, which shares sequence identity with PTEN, dephosphorylates phosphatidylinositol 4, 5-bisphosphate. Proceedings of the National Academy of Sciences of the United States of America, 105, 7970–7975.
Murata, Y., Iwasaki, H., Sasaki, M., Inaba, K., & Okamura, Y. (2005). Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature, 435, 1239–1243.
Murata, Y., & Okamura, Y. (2007). Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2. Journal of Physiology, 583, 875–889.
Murata, Y., Iwasaki, H., Sasaki, M., Inaba, K., & Okamura, Y. (2005). Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature, 435, 1239–1243.
Adams, D. S. (2008). A new tool for tissue engineers: Ions as regulators of morphogenesis during development and regeneration. Tissue Engineering. Part A, 14, 1461–1468.
Chen, J. G., & Rudnick, G. (2000). Permeation and gating residues in serotonin transporter. Proceedings of the National Academy of Sciences of the United States of America, 97, 1044–1049.
Fukumoto, T., Blakely, R., & Levin, M. (2005). Serotonin transporter function is an early step in left-right patterning in chick and frog embryos. Developmental Neuroscience, 27, 349–363.
Hegle, A. P., Marble, D. D., & Wilson, G. F. (2006). A voltage-driven switch for ion-independent signaling by ether-a-go-go K+ channels. Proceedings of the National Academy of Sciences of the United States of America, 103, 2886–2891.
Yang, S. J., Liang, H. L., Ning, G., & Wong-Riley, M. T. (2004). Ultrastructural study of depolarization-induced translocation of NRF-2 transcription factor in cultured rat visual cortical neurons. European Journal of Neuroscience, 19, 1153–1162.
Li, L., Liu, F., Salmonsen, R. A., et al. (2002). PTEN in neural precursor cells: Regulation of migration, apoptosis, and proliferation. Molecular and Cellular Neurosciences, 20, 21–29.
Poo, M. M., & Robinson, K. R. (1977). Electrophoresis of concanavalin-a receptors along embryonic muscle-cell membrane. Nature, 265, 602–605.
Cooper, M. S., Miller, J. P., & Fraser, S. E. (1989). Electrophoretic repatterning of charged cytoplasmic molecules within tissues coupled by gap junctions by externally applied electric fields. Developmental Biology, 132, 179–188.
Fang, K. S., Ionides, E., Oster, G., Nuccitelli, R., & Isseroff, R. R. (1999). Epidermal growth factor receptor relocalization and kinase activity are necessary for directional migration of keratinocytes in DC electric fields. Journal of Cell Science, 112, 1967–1978.
Giugni, T. D., Braslau, D. L., & Haigler, H. T. (1987). Electric field-induced redistribution and postfield relaxation of epidermal growth factor receptors on A431 cells. Journal of Cell Biology, 104, 1291–1297.
Stollberg, J., & Fraser, S. E. (1988). Acetylcholine receptors and concanavalin A-binding sites on cultured Xenopus muscle cells: electrophoresis, diffusion, and aggregation. Journal of Cell Biology, 107, 1397–1408.
Orida, N., & Poo, M. M. (1978). Electrophoretic movement and localisation of acetylcholine receptors in the embryonic muscle cell membrane. Nature, 275, 31–35.
Fukumoto, T., Kema, I. P., & Levin, M. (2005). Serotonin signaling is a very early step in patterning of the left-right axis in chick and frog embryos. Current Biology, 15, 794–803.
Woodruff, R., & Telfer, W. (1980). Electrophoresis of proteins in intercellular bridges. Nature, 286, 84–86.
Korohoda, W., Mycielska, M., Janda, E., & Madeja, Z. (2000). Immediate and long-term galvanotactic responses of Amoeba proteus to dc electric fields. Cell Motility and the Cytoskeleton, 45, 10–26.
Tao, Y., Yan, D., Yang, Q., Zeng, R., & Wang, Y. (2006). Low K+ promotes NF-kappaB/DNA binding in neuronal apoptosis induced by K+ loss. Molecular and Cellular Biology, 26, 1038–1050.
Gillies, R., Martinez-Zaguilan, R., Peterson, E., & Perona, R. (1992). Role of intracellular pH in mammalian cell proliferation. Cellular Physiology and Biochemistry, 2, 159–179.
Uzman, J. A., Patil, S., Uzgare, A. R., & Sater, A. K. (1998). The role of intracellular alkalinization in the establishment of anterior neural fate in Xenopus. Developmental Biology, 193, 10–20.
Schuldiner, S., & Rozengurt, E. (1982). Na+/H+ antiport in Swiss 3 T3 cells: Mitogenic stimulation leads to cytoplasmic alkalinization. Proceedings of the National Academy of Sciences of the United States of America, 79, 7778–7782.
Zhong, M., Kim, S. J., & Wu, C. (1999). Sensitivity of Drosophila heat shock transcription factor to low pH. Journal of Biological Chemistry, 274, 3135–3140.
Lin, H., Xiao, J., Luo, X., et al. (2007). Overexpression HERG K(+) channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-kappaB and inactivation of tumor suppressor Nkx3.1. Journal of Cellular Physiology, 212, 137–147.
Chudotvorova, I., Ivanov, A., Rama, S., et al. (2005). Early expression of KCC2 in rat hippocampal cultures augments expression of functional GABA synapses. Journal of Physiology, 566, 671–679.
Burrone, J., O’Byrne, M., & Murthy, V. N. (2002). Multiple forms of synaptic plasticity triggered by selective suppression of activity in individual neurons. Nature, 420, 414–418.
Beech, J. A. (1997). Bioelectric potential gradients may initiate cell cycling: ELF and zeta potential gradients may mimic this effect. Bioelectromagnetics, 18, 341–348.
Redmann, K., Jenssen, H. L., & Kohler, H. J. (1974). Experimental and functional changes in transmembrane potential and zeta potential of single cultured cells. Experimental Cell Research, 87, 281–289.
Sherbet, G. V., & Lakshmi, M. S. (1974). The surface properties of some human intracranial tumour cell lines in relation to their malignancy. Oncology, 29, 335–347.
James, A. M., Ambrose, E. J., & Lowick, J. H. (1956). Differences between the electrical charge carried by normal and homologous tumour cells. Nature, 177, 576–577.
Weihua, Z., Tsan, R., Schroit, A. J., & Fidler, I. J. (2005). Apoptotic cells initiate endothelial cell sprouting via electrostatic signaling. Cancer Research, 65, 11529–11535.
Acknowledgements
S.S. would like to thank the NSF for funding through the Graduate Research Fellowship Program. D.K. is supported by the NIH through the Tissue Engineering Resource Center (P41 EB002520). M.L. is supported by grants from the NHTSA (DTNH22-06-G-00001) and NIH (GM078484, HD055850-01).
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Sundelacruz, S., Levin, M. & Kaplan, D.L. Role of Membrane Potential in the Regulation of Cell Proliferation and Differentiation. Stem Cell Rev and Rep 5, 231–246 (2009). https://doi.org/10.1007/s12015-009-9080-2
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DOI: https://doi.org/10.1007/s12015-009-9080-2