Polydendrocytes (also known as NG2 glial cells) constitute a fourth major glial cell type in the adult mammalian central nervous system (CNS) that is distinct from other cell types. Although much evidence suggests that these cells are multipotent in vitro, their differentiation potential in vivo under physiological or pathophysiological conditions is still controversial.To follow the fate of polydendrocytes after CNS pathology, permanent middle cerebral artery occlusion (MCAo), a commonly used model of focal cerebral ischemia, was carried out on adult NG2creBAC:ZEG double transgenic mice, in which enhanced green fluorescent protein (EGFP) is expressed in polydendrocytes and their progeny. The phenotype of the EGFP(+) cells was analyzed using immunohistochemistry and the patch-clamp technique 3, 7 and 14 days after MCAo. In sham-operated mice (control), EGFP(+) cells in the cortex expressed protein markers and displayed electrophysiological properties of polydendrocytes and oligodendrocytes. We did not detect any co-labeling of EGFP with neuronal, microglial or astroglial markers in this region, thus proving polydendrocyte unipotent differentiation potential under physiological conditions. Three days after MCAo the number of EGFP(+) cells in the gliotic tissue dramatically increased when compared to control animals, and these cells displayed properties of proliferating cells. However, in later phases after MCAo a large subpopulation of EGFP(+) cells expressed protein markers and electrophysiological properties of astrocytes that contribute to the formation of glial scar. Importantly, some EGFP(+) cells displayed membrane properties typical for neural precursor cells, and moreover these cells expressed doublecortin (DCX)--a marker of newly-derived neuronal cells. Taken together, our data indicate that polydendrocytes in the dorsal cortex display multipotent differentiation potential after focal ischemia.

Department of Cellular Neurophysiology Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic

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Tian D-S, Dong Q, Pan D-J, He Y, Yu Z-Y, et al. Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Res. 2007;1154:206–214. PubMed

Yang Y, Jalal FY, Thompson JF, Walker EJ, Candelario-Jalil E, et al. Tissue inhibitor of metalloproteinases-3 mediates the death of immature oligodendrocytes via TNF-α/TACE in focal cerebral ischemia in mice. J Neuroinflammation. 2011;8:108. PubMed PMC

Pettigrew LC, Kindy MS, Scheff S, Springer JE, Kryscio RJ, et al. Focal cerebral ischemia in the TNFalpha-transgenic rat. J Neuroinflammation. 2008;5:47. PubMed PMC

Nishiyama A. Polydendrocytes: NG2 cells with many roles in development and repair of the CNS. Neuroscientist. 2007;13:62–76. PubMed

Kondo T, Raff M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science. 2000;289:1754–1757. PubMed

Belachew S, Chittajallu R, Aguirre A, Yuan X, Kirby M, et al. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol. 2003;161:169–186. PubMed PMC

Aguirre A, Chittajallu R, Belachew S, Gallo V. NG2-expressing cells in the subventricular zone are type C-like cells and contribute to interneuron generation in the postnatal hippocampus. J Cell Biol. 2004;165:575–589. PubMed PMC

Guo F, Maeda Y, Ma J, Xu J, Horiuchi M, et al. Pyramidal Neurons Are Generated from Oligodendroglial Progenitor Cells in Adult Piriform Cortex. J Neurosci. 2010;30:12036–12049. PubMed PMC

Zhu X, Hill RA, Nishiyama A. NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord. Neuron Glia Biol. 2008;4:19–26. PubMed

Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci. 2008;11:1392–1401. PubMed PMC

Dimou L, Simon C, Kirchhoff F, Takebayashi H, Goetz M. Progeny of Olig2-Expressing Progenitors in the Gray and White Matter of the Adult Mouse Cerebral Cortex. J Neurosci. 2008;28:10434–10442. PubMed PMC

Hampton D, Rhodes K, Zhao C, Franklin R, Fawcett J. The responses of oligodendrocyte precursor cells, astrocytes and microglia to a cortical stab injury, in the brain. Neuroscience. 2004;127:813–820. PubMed

Pivonkova H, Benesova Jana, Benesova J, Butenko O, Chvatal A, et al. Impact of global cerebral ischemia on K+ channel expression and membrane properties of glial cells in the rat hippocampus. Neurochem Int. 2010;57:783–794. PubMed

Trotter J, Karram K, Nishiyama A. NG2 cells: Properties, progeny and origin. Brain Res Rev. 2010;63:72–82. PubMed PMC

Komitova M, Serwanski DR, Richard Lu Q, Nishiyama A. NG2 cells are not a major source of reactive astrocytes after neocortical stab wound injury. Glia. 2011;59:800–809. PubMed PMC

Anderova Miroslava, Vorisek I, Pivonkova H, Benesova Jana, Vargova L, et al. Cell death/proliferation and alterations in glial morphology contribute to changes in diffusivity in the rat hippocampus after hypoxia-ischemia. J Cereb Blood Flow Metab. 2011;31:894–907. PubMed PMC

Muskhelishvili L, Latendresse JR, Kodell RL, Henderson EB. Evaluation of Cell Proliferation in Rat Tissues with BrdU, PCNA, Ki-67(MIB-5) Immunohistochemistry and In Situ Hybridization for Histone mRNA. Journal of Histochemistry & Cytochemistry. 2003;51:1681–1688. PubMed

Zhu X, Bergles DE, Nishiyama A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development. 2008;135:145–157. PubMed

Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28:264–278. PubMed PMC

Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx: the journal of the American Society for Experimental NeuroTherapeutics. 2005;2:396–409. PubMed PMC

Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organisation. Histol Histopathol. 2005;20:665–671. PubMed

Simon C, Götz M, Dimou L. Progenitors in the adult cerebral cortex: Cell cycle properties and regulation by physiological stimuli and injury. Glia. 2011;59:869–881. PubMed

Chen P-H, Cai W-Q, Wang L-Y, Deng Q-Y. A morphological and electrophysiological study on the postnatal development of oligodendrocyte precursor cells in the rat brain. Brain Res. 2008;1243:27–37. PubMed

Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci. 2002;5:308–315. PubMed

Komitova M, Zhu X, Serwanski DR, Nishiyama A. NG2 cells are distinct from neurogenic cells in the postnatal mouse subventricular zone. J Comp Neurol. 2009;512:702–716. PubMed PMC

Nishiyama A, Komitova M, Suzuki R, Zhu X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci. 2009;10:9–22. PubMed

Xie M, Lynch DT Schools GP, Feustel PJ, Kimelberg HK, et al. Sodium channel currents in rat hippocampal NG2 glia: Characterization and contribution to resting membrane potential. Neuroscience. 2007;150:853–862. PubMed

Schools GP, Zhou M, Kimelberg HK. Electrophysiologically “complex” glial cells freshly isolated from the hippocampus are immunopositive for the chondroitin sulfate proteoglycan NG2. J Neurosci Res. 2003;73:765–777. PubMed

Knutson P, Ghiani CA, Zhou JM, Gallo V, McBain CJ. K+ channel expression and cell proliferation are regulated by intracellular sodium and membrane depolarization in oligodendrocyte progenitor cells. J Neurosci. 1997;17:2669–2682. PubMed PMC

Chvatal A, Anderova Miroslava, Sykova E. Analysis of K+ accumulation reveals privileged extracellular region in the vicinity of glial cells in situ. J Neurosci Res. 2004;78:668–682. PubMed

Karram K, Goebbels S, Schwab M, Jennissen K, Seifert G, et al. NG2-expressing cells in the nervous system revealed by the NG2-EYFP-knockin mouse. genesis. 2008;46:743–757. PubMed

Tatsumi K, Takebayashi H, Manabe T, Tanaka KF, Makinodan M, et al. Genetic fate mapping of Olig2 progenitors in the injured adult cerebral cortex reveals preferential differentiation into astrocytes. J Neurosci Res. 2008;86:3494–3502. PubMed

Tripathi RB, Rivers LE, Young KM, Jamen F, Richardson WD. NG2 Glia Generate New Oligodendrocytes But Few Astrocytes in a Murine Experimental Autoimmune Encephalomyelitis Model of Demyelinating Disease. J Neurosci. 2010;30:16383–16390. PubMed PMC

Zawadzka M, Rivers LE, Fancy SPJ, Zhao C, Tripathi R, et al. CNS-Resident Glial Progenitor/Stem Cells Produce Schwann Cells as well as Oligodendrocytes during Repair of CNS Demyelination. Stem Cell. 2010;6:578–590. PubMed PMC

Wohl SG, Schmeer CW, Friese T, Witte OW, Isenmann S. In Situ Dividing and Phagocytosing Retinal Microglia Express Nestin, Vimentin, and NG2 In Vivo. PLoS ONE. 2011;6:e22408. PubMed PMC

Zhu L, Lu J, Tay SSW, Jiang H, He BP. Induced NG2 expressing microglia in the facial motor nucleus after facial nerve axotomy. NSC. 2010;166:842–851. PubMed

Gao Q, Lu J, Huo Y, Baby N, Ling EA, et al. NG2, a member of chondroitin sulfate proteoglycans family mediates the inflammatory response of activated microglia. NSC. 2010;165:386–394. PubMed

Bulloch K, Miller MM, Gal-Toth J, Milner TA, Gottfried-Blackmore A, et al. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J Comp Neurol. 2008;508:687–710. PubMed

Nishiyama A, Yu M, Drazba JA, Tuohy VK. Normal and reactive NG2+ glial cells are distinct from resting and activated microglia. J Neurosci Res. 1997;48:299–312. PubMed

Jones LL, Yamaguchi Y, Stallcup WB, Tuszynski MH. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci. 2002;22:2792–2803. PubMed PMC

Anderova Miroslava, Antonova T, Petrik D, Neprasova Helena, Chvatal A, et al. Voltage-dependent potassium currents in hypertrophied rat astrocytes after a cortical stab wound. Glia. 2004;48:311–326. PubMed

Lacar . Front Neurosci; 2010. Imaging and recording subventricular zone progenitor cells in live tissue of postnatal mice. PubMed PMC

Carlen M, Meletis K, Göritz C, Darsalia V, Evergren E, et al. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci. 2009;12:259–267. PubMed

Zhu X, Hill RA, Dietrich D, Komitova M, Suzuki R, et al. Age-dependent fate and lineage restriction of single NG2 cells. Development. 2011;138:745–753. PubMed PMC

Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE. NG2+ CNS Glial Progenitors Remain Committed to the Oligodendrocyte Lineage in Postnatal Life and following Neurodegeneration. Proc Natl Acad Sci USA. 2010;68:668–681. PubMed PMC

Matute C, Alberdi E, Domercq M, Sánchez-Gómez M-V, Pérez-Samartín A, et al. Excitotoxic damage to white matter. J Anat. 2007;210:693–702. PubMed PMC

Richardson WD, Young KM, Tripathi RB, McKenzie I. NG2-glia as Multipotent Neural Stem Cells: Fact or Fantasy? Proc Natl Acad Sci USA. 2011;70:661–673. PubMed PMC

Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, et al. A Pericyte Origin of Spinal Cord Scar Tissue. Science. 2011;333:238–242. PubMed

Hamilton TG, Klinghoffer RA, Corrin PD, Soriano P. Evolutionary Divergence of Platelet-Derived Growth Factor Alpha Receptor Signaling Mechanisms. Molecular and Cellular Biology. 2003;23:4013–4025. PubMed PMC

Bondjers C, He L, Takemoto M, Norlin J, Asker N, et al. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 2006;20:1703–1705. PubMed

Montiel-Eulefi E, Nery AA, Rodrigues LC, Sánchez R, Romero F, et al. Neural differentiation of rat aorta pericyte cells. Cytometry A. 2012;81:65–71. PubMed

Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, et al. Notch receptor activation inhibits oligodendrocyte differentiation. Proc Natl Acad Sci USA. 1998;21:63–75. PubMed

Yamamoto S, Nagao M, Sugimori M, Kosako H, Nakatomi H, et al. Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord. J Neurosci. 2001;21:9814–9823. PubMed PMC

Grandbarbe L, Bouissac J, Rand M, Hrabé de Angelis M, Artavanis-Tsakonas S, et al. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development. 2003;130:1391–1402. PubMed

Sellers DL, Maris DO, Horner PJ. Postinjury Niches Induce Temporal Shifts in Progenitor Fates to Direct Lesion Repair after Spinal Cord Injury. J Neurosci. 2009;29:6722–6733. PubMed PMC

White BD, Nathe RJ, Maris DO, Nguyen NK, Goodson JM, et al. Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells. 2010;28:297–307. PubMed PMC

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