Abstract
The functional and structural integrity of the nervous system depends on the coordinated action of neurons and glial cells. Phenomena like synaptic activity, conduction of action potentials, and neuronal growth and regeneration, to name a few, are fine tuned by glial cells. Furthermore, the active role of glial cells in the regulation of neuronal functions is underscored by several conditions in which specific mutation affecting the glia results in axonal dysfunction. We have shown that Schwann cells (SCs), the peripheral nervous system glia, supply axons with ribosomes, and since proteins underlie cellular programs or functions, this dependence of axons from glial cells provides a new and unexplored dimension to our understanding of the nervous system. Recent evidence has now established a new modality of intercellular communication through extracellular vesicles. We have already shown that SC-derived extracellular vesicles known as exosomes enhance axonal regeneration, and increase neuronal survival after pro-degenerative stimuli. Therefore, the biology nervous system will have to be reformulated to include that the phenotype of a nerve cell results from the contribution of two nuclei, with enormous significance for the understanding of the nervous system in health and disease.
Similar content being viewed by others
References
Abounit S, Zurzolo C (2012) Wiring through tunneling nanotubes–from electrical signals to organelle transfer. J Cell Sci 125:1089–1098
Aguayo AJ, Nair CP, Bray GM (1971) Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol 24(2):106–116
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345. doi:10.1038/nbt.1807
Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Brański P, Ratajczak MZ, Zembala M (2006) Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 55:808–818
Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, Hetz C, Twiss JL, Alvarez J, Court FA (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci 31(3):966–978
Beirowski B, Babetto E, Golden JP, Chen Y-J, Yang K, Gross RW (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17(10):1351–1361
Berdan RC, Easaw JC, Wang R (1993) Alterations in membrane potential after axotomy at different distances from the soma of an identified neuron and the effect of depolarization on neurite outgrowth and calcium channel expression. J Neurophysiol 69(1):151–164
Berger P, Niemann A, Suter U (2006) Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease). Glia 54(4):243–257
Blesch A, Tuszynski MH (2009) Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci 32:41–47
Bradley RS, Brown AM (1990) The proto-oncogene int-1 encodes a secreted protein associated with the extracellular matrix. EMBO J 9(5):1569–1575
Bray GM, Rasminsky M, Aguayo AJ (1981) Interactions between axons and their sheath cells. Annu Rev Neurosci 4:127–162
Brown AM, Evans RD, Black J, Ransom BR (2012) Schwann cell glycogen selectively supports myelinated axon function. Ann Neurol 72(3):406–418
Calixto A, Jara JS, Court FA (2012) Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss. PLoS Genet 8(12):e1003141
Carson JH, Kwon S, Barbarese E (1998) RNA trafficking in myelinating cells. Curr Opin Neurobiol 8(5):607–612
Chen Z-L, Yu W-M, Strickland S (2007) Peripheral regeneration. Ann Rev Neurosci 30:209–233
Collyer E, Catenaccio A, Lemaitre D, Diaz P, Valenzuela V, Bronfman F, Court FA (2014) Sprouting of axonal collaterals after spinal cord injury is prevented by delayed axonal degeneration. Exp Neurol 261:451–461
Court F, Alvarez J (2000) Nerve regeneration in Wld(s) mice is normalized by actinomycin D. Brain Res 867:1–8
Court FA, Alvarez J (2005) Local regulation of the axonal phenotype, a case of merotrophism. Biol Res 38(4):365–374
Court FA, Coleman MP (2012) Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci 35(6):364–372
Court FA, Sherman DL, Pratt T, Garry EM, Ribchester RR, Cottrell DF, Fleetwood-Walker SM, Brophy PJ (2004a) Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature 431:191–195
Court FA, Sherman DL, Pratt T, Garry EM, Ribchester RR, Cottrell DF (2004b) Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature 431(7005):191–195
Court FA, Wrabetz L, Feltri ML (2006) Basal lamina: schwann cells wrap to the rhythm of space-time. Curr Opin Neurobiol 16:501–507
Court FA, Hendriks WT, MacGillavry HD, Alvarez J, van Minnen J (2008) Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J Neurosci 28(43):11024–11029
Court FA, Midha R, Cisterna BA, Grochmal J, Shakhbazau A, Hendriks WT, Van Minnen J (2011) Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons. Glia 59(10):1529–1539
Cutillo V, Montagnese P, Gremo F, Casola L, Giuditta A (1983) Origin of axoplasmic RNA in the squid giant fiber. Neurochem Res 8(12):1621–1634
Debanne D, Rama S (2011) Astrocytes shape axonal signaling. Sci Signal 4(162):pe11
Fields RD, Ni Y (2010) Nonsynaptic communication through ATP release from volume-activated anion channels in axons. Sci Signal 3:ra73
Filbin MT (2003) Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 4(9):703–713
Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124(Pt 3):447–458. doi:10.1242/jcs.074088
Fröhlich D, Kuo WP, Frühbeis C, Sun JJ, Zehendner CM, Luhmann HJ, Pinto S, Toedling J, Trotter J, Krämer-Albers EM (2014) Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond B 369(1652):20130510
Frühbeis C, Fröhlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604
Gehler S, Gallo G, Veien E, Letourneau PC (2004) p75 neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity. J Neurosci 24:4363–4372
Glenn TD, Talbot WS (2013) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23:1041–1048
Greco V, Hannus M, Eaton S (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106(5):633–645
Grimmelikhuijzen CJ, Hauser F (2012) Mini-review: the evolution of neuropeptide signaling. Regul Pept 177(Suppl):S6–S9
Gross JC, Chaudhary V, Bartscherer K, Boutros M (2012) Active Wnt proteins are secreted on exosomes. Nat Cell Biol 14(10):1036–1045. doi:10.1038/ncb2574
Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97(2):329–339
Hartline DK, Colman DR (2007) Rapid conduction and the evolution of giant axons and myelinated fibers. Curr Biol 17(1):R29–R35
Holt CE, Schuman EM (2013) The central dogma decentralized: new perspectives on RNA function and local translation in neurons. Neuron 80(3):648–657
Ilieva H, Polymenidou M, Cleveland DW (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187(6):761–772
Jeftinija SD, Jeftinija KV (1998) ATP stimulates release of excitatory amino acids from cultured Schwann cells. Neuroscience 82:927–934
Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56:1552–1565
Kidd GJ, Ohno N, Trapp BD (2013) Biology of Schwann cells. Handb Clin Neurol 115:55–79
Kijima M, Yamaguchi T, Ishifune C, Maekawa Y, Koyanagi A, Yagita H, Chiba S, Kishihara K, Shimada M, Yasutomo K (2008) Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction. Proc Natl Acad Sci USA 105:7010–7015. doi:10.1073/pnas.0709919105
Koenig E, Martin R (1996) Cortical plaque-like structures identify ribosome-containing domains in the Mauthner cell axon. J Neurosci 16(4):1400–1411
Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, Budnik V (2009) Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell 139:393–404
Krämer-Albers E-M, Bretz N, Tenzer S, Winterstein C, Möbius W, Berger H, Nave K-A, Schild H, Trotter J (2007) Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin Appl 1(11):1446–1461
Liu GJ, Bennett MR (2003) ATP secretion from nerve trunks and Schwann cells mediated by glutamate. NeuroReport 14(16):2079–2083
Liu GJ, Werry EL, Bennett MR (2005) Secretion of ATP from Schwann cells in response to uridine triphosphate. Eur J Neurosci 21(1):151–160
Lopez-Verrilli MA, Court FA (2012) Transfer of vesicles from schwann cells to axons: a novel mechanism of communication in the peripheral nervous system. Front Physiol 3:205
Lopez-Verrilli MA, Court FA (2013) Exosomes: mediators of communication in eukaryotes. Biol Res 46:5–11
Lopez-Verrilli MA, Picou F, Court FA (2013) Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61(11):1795–1806
Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma PL (2013) Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol 698:6–18
Nave K-A, Trapp BD (2008) Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 31(1):535–561
Orellana JA, Sanchez HA, Schalper KA, Figueroa V, Saez JC (2012) Regulation of intercellular calcium signaling through calcium interactions with connexin-based channels. Adv Exp Med Biol 740:777–794
Pereira JA, Lebrun-Julien F, Suter U (2012) Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci 35:123–134
Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20(5):847–856
Revest JM, Faivre-Sarrailh C, Maeda N, Noda M, Schachner M, Rougon G (1999) The interaction between F3 immunoglobulin domains and protein tyrosine phosphatases zeta/beta triggers bidirectional signalling between neurons and glial cells. Eur J Neurosci 11(4):1134–1147
Rigaud M, Gemes G, Barabas M-E, Chernoff DI, Abram SE, Stucky CL, Hogan QH (2008) Species and strain differences in rodent sciatic nerve anatomy: implications for studies of neuropathic pain. Pain. 136:188–201
Russo I, Bubacco L, Greggio E (2012) Exosomes-associated neurodegeneration and progression of Parkinson’s disease. Am J Neurodegener Dis 1(3):217–225
Rustom A, Saffrich R, Markovic I, Walther P, Gerdes H-H (2004) Nanotubular highways for intercellular organelle transport. Science (New York, N.Y.) 303(5660):1007–1010
Samara C, Poirot O, Domènech-Estévez E, Chrast R (2013) Neuronal activity in the hub of extrasynaptic Schwann cell-axon interactions. Front Cell Neurosci. doi:10.3389/fncel.2013.00228
Schmitte R, Tipold A, Stein VM, Schenk H, Flieshardt C, Grothe C, Haastert K (2010) Genetically modified canine Schwann cells–In vitro and in vivo evaluation of their suitability for peripheral nerve tissue engineering. J Neurosci Methods 186(2):202–208. doi:10.1016/j.jneumeth.2009.11.023
Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476
Sotelo-Silveira JR, Calliari A, Cárdenas M, Koenig E, Sotelo JR (2004) Myosin Va and kinesin II motor proteins are concentrated in ribosomal domains (periaxoplasmic ribosomal plaques) of myelinated axons. J Neurobiol 60(2):187–196
Tapia M, Inestrosa NC, Alvarez J (1995) Early axonal regeneration: repression by Schwann cells and a protease? Exp Neurol 131:124–132
Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2(8):569–579
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659
Valenzuela V, Collyer E, Armentano D, Parsons GB, Court FA, Hetz C (2012) Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis 3:e272
Verderio C, Bianco F, Blanchard MP, Bergami M, Canossa M, Scarfone E et al (2006) Cross talk between vestibular neurons and Schwann cells mediates BDNF release and neuronal regeneration. Brain Cell Biol 35:187–201. doi:10.1007/s11068-007-9011-6
Villegas R, Martinez NW, Lillo J, Pihan P, Hernandez D, Twiss JL, Court FA (2014) Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction. J Neurosci 34(21):7179–7189
Voas MG, Glenn TD, Raphael AR, Talbot WS (2009) Schwann cells inhibit ectopic clustering of axonal sodium channels. J Neurosci 29(46):14408–14414
Wake H, Lee PR, Fields RD (2011) Control of local protein synthesis and initial events in myelination by action potentials. Science 333:1647–1651. doi:10.1126/science.1206998
Waller A (1850) Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Philos Trans R Soc Lond 140:423–429
Wang D, Sun T (2010) Neural plasticity and functional recovery of human central nervous system with special reference to spinal cord injury. Spinal Cord 49:486
Yamazaki Y, Hozumi Y, Kaneko K, Sugihara T, Fujii S, Goto K, Kato H (2008) Modulatory effects of oligodendrocytes on the conduction velocity of action potentials along axons in the alveus of the rat hippocampal CA1 region. Neuron Glia Biol 3(04):325–334
Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627
Yoo S, van Niekerk EA, Merianda TT, Twiss JL (2010) Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration. Exp Neurol 223:19–27
Zadori D, Klivenyi P, Szalardy L, Fulop F, Toldi J, Vecsei L (2012) Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: novel therapeutic strategies for neurodegenerative disorders. J Neurol Sci 322:187–191
Zhang J, Zhao F, Wu G, Li Y, Jin X (2010) Functional and histological improvement of the injured spinal cord following transplantation of Schwann cells transfected with NRG1 gene. Anat Rec (Hoboken) 293:1933–1946
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lopez-Leal, R., Court, F.A. Schwann Cell Exosomes Mediate Neuron–Glia Communication and Enhance Axonal Regeneration. Cell Mol Neurobiol 36, 429–436 (2016). https://doi.org/10.1007/s10571-015-0314-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-015-0314-3