Neurochemical Research

, Volume 36, Issue 9, pp 1601–1611 | Cite as

There is More to a Lipid than just Being a Fat: Sphingolipid-Guided Differentiation of Oligodendroglial Lineage from Embryonic Stem Cells

  • Erhard Bieberich


Dr. Robert K. Yu’s research showed for the first time that the composition of glycosphingolipids is tightly regulated during embryo development. Studies in our group showed that the glycosphingolipid precursor ceramide is also critical for stem cell differentiation and apoptosis. Our new studies suggest that ceramide and its derivative, sphingosine-1-phosphate (S1P), act synergistically on embryonic stem (ES) cell differentiation. When using neural precursor cells (NPCs) derived from ES cells for transplantation, residual pluripotent stem (rPS) cells pose a significant risk of tumor formation after stem cell transplantation. We show here that rPS cells did not express the S1P receptor S1P1, which left them vulnerable to ceramide or ceramide analog (N-oleoyl serinol or S18)-induced apoptosis. In contrast, ES cell-derived NPCs expressed S1P1 and were protected in the presence of S1P or its pro-drug analog FTY720. Consistent with previous studies, FTY720-treated NPCs differentiated predominantly toward oligodendroglial lineage as tested by the expression of the oligodendrocyte precursor cell (OPC) markers Olig2 and O4. As the consequence, a combined administration of S18 and FTY720 to differentiating ES cells eliminated rPS cells and promoted oligodendroglial differentiation. In addition, we show that this combination promoted differentiation of ES cell-derived NPCs toward oligodendroglial lineage in vivo after transplantation into mouse brain.


Ceramide Sphingosine-1-phosphate Embryonic stem cells Apoptosis Differentiation Oligodendrocyte precursors 



Atypical PKC


Embryoid body


EB-derived cell


Embryonic stem


Induced oligodendrocyte precursor cell


Myelin basic protein


Neural progenitor


Neural precursor cell


Oligodendrocyte precursor cell


Prostate apoptosis response 4


Residual pluripotent stem




N-oleoyl serinol



This work was supported in part by the NIH grants R01AG034389 and R01NS046835 to EB. The author also acknowledges institutional support (under directorship of Dr. Lin Mei) at the Medical College of Georgia/Georgia Health Sciences University, Augusta, GA. We are thankful to the Imaging Core Facility (under directorship of Dr. Paul McNeil) for assistance with confocal microscopy.


  1. 1.
    Strathmann FG, Wang X, Mayer-Proschel M (2007) Identification of two novel glial-restricted cell populations in the embryonic telencephalon arising from unique origins. BMC Dev Biol 7:33PubMedCrossRefGoogle Scholar
  2. 2.
    Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99:2344–2349PubMedCrossRefGoogle Scholar
  3. 3.
    Bieberich E, Silva J, Wang G, Krishnamurthy K, Condie BG (2004) Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J Cell Biol 167:723–734PubMedCrossRefGoogle Scholar
  4. 4.
    Brustle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID, McKay RD (1999) Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285:754–756PubMedCrossRefGoogle Scholar
  5. 5.
    Duncan ID (2005) Oligodendrocytes and stem cell transplantation: their potential in the treatment of leukoencephalopathies. J Inherit Metab Dis 28:357–368PubMedCrossRefGoogle Scholar
  6. 6.
    Perez-Bouza A, Glaser T, Brustle O (2005) ES cell-derived glial precursors contribute to remyelination in acutely demyelinated spinal cord lesions. Brain Pathol 15:208–216PubMedCrossRefGoogle Scholar
  7. 7.
    Hu BY, Du ZW, Zhang SC (2009) Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc 4:1614–1622PubMedCrossRefGoogle Scholar
  8. 8.
    Kiel ME, Chen CP, Sadowski D, McKinnon RD (2008) Stem cell-derived therapeutic myelin repair requires 7% cell replacement. Stem Cells 26:2229–2236PubMedCrossRefGoogle Scholar
  9. 9.
    Maire CL, Buchet D, Kerninon C, Deboux C, Baron-Van Evercooren A, Nait-Oumesmar B (2009) Directing human neural stem/precursor cells into oligodendrocytes by overexpression of Olig2 transcription factor. J Neurosci Res 87:3438–3446PubMedCrossRefGoogle Scholar
  10. 10.
    Goldman JE, Hirano M, Yu RK, Seyfried TN (1984) GD3 ganglioside is a glycolipid characteristic of immature neuroectodermal cells. J Neuroimmunol 7:179–192PubMedCrossRefGoogle Scholar
  11. 11.
    Yu RK (1994) Development regulation of ganglioside metabolism. Prog Brain Res 101:31–44PubMedCrossRefGoogle Scholar
  12. 12.
    Suetake K, Liour SS, Tencomnao T, Yu RK (2003) Expression of gangliosides in an immortalized neural progenitor/stem cell line. J Neurosci Res 74:769–776PubMedCrossRefGoogle Scholar
  13. 13.
    Cochran FB, Ledeen RW, Yu RK (1982) Gangliosides and proteins in developing chicken brain myelin. Brain Res 282:27–32PubMedGoogle Scholar
  14. 14.
    Yu RK, Macala LJ, Taki T, Weinfield HM, Yu FS (1988) Developmental changes in ganglioside composition and synthesis in embryonic rat brain. J Neurochem 50:1825–1829PubMedCrossRefGoogle Scholar
  15. 15.
    Yu RK, Macala LJ, Farooq M, Sbaschnig-Agler M, Norton WT, Ledeen RW (1989) Ganglioside and lipid composition of bulk-isolated rat and bovine oligodendroglia. J Neurosci Res 23:136–141PubMedCrossRefGoogle Scholar
  16. 16.
    Zeng G, Gao L, Freischutz B, Tokuda A, Yu RK (1998) Developmental expression of rat brain GD3-and GT3-synthases. Ann N Y Acad Sci 845:430PubMedCrossRefGoogle Scholar
  17. 17.
    Ngamukote S, Yanagisawa M, Ariga T, Ando S, Yu RK (2007) Developmental changes of glycosphingolipids and expression of glycogenes in mouse brains. J Neurochem 103:2327–2341PubMedCrossRefGoogle Scholar
  18. 18.
    Liour SS, Yu RK (2002) Differential effects of three inhibitors of glycosphingolipid biosynthesis on neuronal differentiation of embryonal carcinoma stem cells. Neurochem Res 27:1507–1512PubMedCrossRefGoogle Scholar
  19. 19.
    Nakatani Y, Yanagisawa M, Suzuki Y, Yu RK (2010) Characterization of GD3 ganglioside as a novel biomarker of mouse neural stem cells. Glycobiology 20:78–86PubMedCrossRefGoogle Scholar
  20. 20.
    Liour SS, Kapitonov D, Yu RK (2000) Expression of gangliosides in neuronal development of P19 embryonal carcinoma stem cells. J Neurosci Res 62:363–373PubMedCrossRefGoogle Scholar
  21. 21.
    Liour SS, Kraemer SA, Dinkins MB, Su CY, Yanagisawa M, Yu RK (2006) Further characterization of embryonic stem cell-derived radial glial cells. Glia 53:43–56PubMedCrossRefGoogle Scholar
  22. 22.
    Wang G, Silva J, Krishnamurthy K, Tran E, Condie BG, Bieberich E (2005) Direct binding to ceramide activates protein kinase Czeta before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J Biol Chem 280:26415–26424PubMedCrossRefGoogle Scholar
  23. 23.
    Bieberich E, Freischutz B, Suzuki M, Yu RK (1999) Differential effects of glycolipid biosynthesis inhibitors on ceramide-induced cell death in neuroblastoma cells. J Neurochem 72:1040–1049PubMedCrossRefGoogle Scholar
  24. 24.
    Bieberich E, Kawaguchi T, Yu RK (2000) N-acylated serinol is a novel ceramide mimic inducing apoptosis in neuroblastoma cells. J Biol Chem 275:177–181PubMedCrossRefGoogle Scholar
  25. 25.
    Bieberich E, MacKinnon S, Silva J, Yu RK (2001) Regulation of apoptosis during neuronal differentiation by ceramide and b-series complex gangliosides. J Biol Chem 276:44396–44404PubMedCrossRefGoogle Scholar
  26. 26.
    Bieberich E, MacKinnon S, Silva J, Noggle S, Condie BG (2003) Regulation of cell death in mitotic neural progenitor cells by asymmetric distribution of prostate apoptosis response 4 (PAR-4) and simultaneous elevation of endogenous ceramide. J Cell Biol 162:469–479PubMedCrossRefGoogle Scholar
  27. 27.
    Bieberich E (2004) Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: review and hypothesis. Glycoconj J 21:315–327PubMedCrossRefGoogle Scholar
  28. 28.
    Krishnamurthy K, Wang G, Silva J, Condie BG, Bieberich E (2007) Ceramide regulates atypical PKC{zeta}/{lambda}-mediated cell polarity in primitive ectoderm cells: a novel function of sphingolipids in morphogenesis. J Biol Chem 282:3379–3390PubMedCrossRefGoogle Scholar
  29. 29.
    Krishnamurthy K, Dasgupta S, Bieberich E (2007) Development and characterization of a novel anti-ceramide antibody. J Lipid Res 48:968–975PubMedCrossRefGoogle Scholar
  30. 30.
    Bieberich E (2008) Smart drugs for smarter stem cells: making SENSe (sphingolipid-enhanced neural stem cells) of ceramide. Neurosignals 16:124–139PubMedCrossRefGoogle Scholar
  31. 31.
    Bieberich E (2008) Ceramide signaling in cancer and stem cells. Future Lipidol 3:273–300PubMedCrossRefGoogle Scholar
  32. 32.
    Wang G, Krishnamurthy K, Chiang YW, Dasgupta S, Bieberich E (2008) Regulation of neural progenitor cell motility by ceramide and potential implications for mouse brain development. J Neurochem 106:718–733PubMedCrossRefGoogle Scholar
  33. 33.
    Wang G, Silva J, Dasgupta S, Bieberich E (2008) Long-chain ceramide is elevated in presenilin 1 (PS1M146 V) mouse brain and induces apoptosis in PS1 astrocytes. Glia 56:449–456PubMedCrossRefGoogle Scholar
  34. 34.
    Wang G, Krishnamurthy K, Umapathy NS, Verin AD, Bieberich E (2009) The carboxyl-terminal domain of atypical protein kinase Czeta binds to ceramide and regulates junction formation in epithelial cells. J Biol Chem 284:14469–14475PubMedCrossRefGoogle Scholar
  35. 35.
    Yanai J, Doetchman T, Laufer N, Maslaton J, Mor-Yosef S, Safran A, Shani M, Sofer D (1995) Embryonic cultures but not embryos transplanted to the mouse’s brain grow rapidly without immunosuppression. Int J Neurosci 81:21–26PubMedCrossRefGoogle Scholar
  36. 36.
    Wakitani S, Takaoka K, Hattori T, Miyazawa N, Iwanaga T, Takeda S, Watanabe TK, Tanigami A (2003) Embryonic stem cells injected into the mouse knee joint form teratomas and subsequently destroy the joint. Rheumatology (Oxford) 42:162–165CrossRefGoogle Scholar
  37. 37.
    Teramoto K, Hara Y, Kumashiro Y, Chinzei R, Tanaka Y, Shimizu-Saito K, Asahina K, Teraoka H, Arii S (2005) Teratoma formation and hepatocyte differentiation in mouse liver transplanted with mouse embryonic stem cell-derived embryoid bodies. Transplant Proc 37:285–286PubMedCrossRefGoogle Scholar
  38. 38.
    Swijnenburg RJ, Tanaka M, Vogel H, Baker J, Kofidis T, Gunawan F, Lebl DR, Caffarelli AD, de Bruin JL, Fedoseyeva EV, Robbins RC (2005) Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation 112:I166–I172PubMedGoogle Scholar
  39. 39.
    Sanchez-Pernaute R, Studer L, Ferrari D, Perrier A, Lee H, Vinuela A, Isacson O (2005) Long-term survival of dopamine neurons derived from parthenogenetic primate embryonic stem cells (cyno-1) after transplantation. Stem Cells 23:914–922PubMedCrossRefGoogle Scholar
  40. 40.
    Kim D, Gu Y, Ishii M, Fujimiya M, Qi M, Nakamura N, Yoshikawa T, Sumi S, Inoue K (2003) In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cell. Pancreas 27:e34–e41PubMedCrossRefGoogle Scholar
  41. 41.
    Fujikawa T, Oh SH, Pi L, Hatch HM, Shupe T, Petersen BE (2005) Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. Am J Pathol 166:1781–1791PubMedCrossRefGoogle Scholar
  42. 42.
    Fong SP, Tsang KS, Chan AB, Lu G, Poon WS, Li K, Baum LW, Ng HK (2007) Trophism of neural progenitor cells to embryonic stem cells: neural induction and transplantation in a mouse ischemic stroke model. J Neurosci Res 85:1851–1862PubMedCrossRefGoogle Scholar
  43. 43.
    Choi D, Oh HJ, Chang UJ, Koo SK, Jiang JX, Hwang SY, Lee JD, Yeoh GC, Shin HS, Lee JS, Oh B (2002) In vivo differentiation of mouse embryonic stem cells into hepatocytes. Cell Transplant 11:359–368PubMedGoogle Scholar
  44. 44.
    Bielby RC, Boccaccini AR, Polak JM, Buttery LD (2004) In vitro differentiation and in vivo mineralization of osteogenic cells derived from human embryonic stem cells. Tissue Eng 10:1518–1525PubMedGoogle Scholar
  45. 45.
    Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U (2004) Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci 45:4251–4255PubMedCrossRefGoogle Scholar
  46. 46.
    Baker M (2009) Stem cells: fast and furious. Nature 458:962–965PubMedCrossRefGoogle Scholar
  47. 47.
    Leor J, Gerecht S, Cohen S, Miller L, Holbova R, Ziskind A, Shachar M, Feinberg MS, Guetta E, Itskovitz-Eldor J (2007) Human embryonic stem cell transplantation to repair the infarcted myocardium. Heart 93:1278–1284PubMedCrossRefGoogle Scholar
  48. 48.
    Blum B, Benvenisty N (2008) The tumorigenicity of human embryonic stem cells. Adv Cancer Res 100:133–158PubMedCrossRefGoogle Scholar
  49. 49.
    Lee AS, Tang C, Cao F, Xie X, van der Bogt K, Hwang A, Connolly AJ, Robbins RC, Wu JC (2009) Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle 8:2608–2612PubMedCrossRefGoogle Scholar
  50. 50.
    Fong CY, Gauthaman K, Bongso A (2010) Teratomas from pluripotent stem cells: a clinical hurdle. J Cell Biochem 111:769–781PubMedCrossRefGoogle Scholar
  51. 51.
    Kuznetsov SA, Cherman N, Robey PG (2010) In vivo bone formation by progeny of human embryonic stem cells. Stem Cells Dev. doi: 10.1089/scd.2009.0501
  52. 52.
    Wang NK, Tosi J, Kasanuki JM, Chou CL, Kong J, Parmalee N, Wert KJ, Allikmets R, Lai CC, Chien CL, Nagasaki T, Lin CS, Tsang SH (2010) Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa. Transplantation 89:911–919PubMedCrossRefGoogle Scholar
  53. 53.
    Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50(Suppl):S91–S96PubMedCrossRefGoogle Scholar
  54. 54.
    Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150PubMedCrossRefGoogle Scholar
  55. 55.
    Hait NC, Oskeritzian CA, Paugh SW, Milstien S, Spiegel S (2006) Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 1758:2016–2026PubMedCrossRefGoogle Scholar
  56. 56.
    Futerman AH, Hannun YA (2004) The complex life of simple sphingolipids. EMBO Rep 5:777–782PubMedCrossRefGoogle Scholar
  57. 57.
    Merrill AH Jr, Schmelz EM, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, Riley RT, Voss KA, Wang E (1997) Sphingolipids–the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol 142:208–225PubMedCrossRefGoogle Scholar
  58. 58.
    Edsall LC, Pirianov GG, Spiegel S (1997) Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 17:6952–6960PubMedGoogle Scholar
  59. 59.
    Fyrst H, Saba JD (2010) An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 6:489–497PubMedCrossRefGoogle Scholar
  60. 60.
    Bieberich E, Hu B, Silva J, MacKinnon S, Yu RK, Fillmore H, Broaddus WC, Ottenbrite RM (2002) Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells. Cancer Lett 181:55–64PubMedCrossRefGoogle Scholar
  61. 61.
    Osinde M, Mullershausen F, Dev KK (2007) Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 52:1210–1218PubMedCrossRefGoogle Scholar
  62. 62.
    Coelho RP, Payne SG, Bittman R, Spiegel S, Sato-Bigbee C (2007) The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 323:626–635PubMedCrossRefGoogle Scholar
  63. 63.
    Saini HS, Coelho RP, Goparaju SK, Jolly PS, Maceyka M, Spiegel S, Sato-Bigbee C (2005) Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J Neurochem 95:1298–1310PubMedCrossRefGoogle Scholar
  64. 64.
    Hojjati MR, Li Z, Jiang XC (2005) Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochim Biophys Acta 1737:44–51PubMedGoogle Scholar
  65. 65.
    Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25:11113–11121PubMedCrossRefGoogle Scholar
  66. 66.
    Zhou H, Summers SA, Birnbaum MJ, Pittman RN (1998) Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J Biol Chem 273:16568–16575PubMedCrossRefGoogle Scholar
  67. 67.
    Jung CG, Kim HJ, Miron VE, Cook S, Kennedy TE, Foster CA, Antel JP, Soliven B (2007) Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 55:1656–1667PubMedCrossRefGoogle Scholar
  68. 68.
    Hsieh HL, Wu CB, Sun CC, Liao CH, Lau YT, Yang CM (2006) Sphingosine-1-phosphate induces COX-2 expression via PI3 K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells. J Cell Physiol 207:757–766PubMedCrossRefGoogle Scholar
  69. 69.
    Wong RC, Tellis I, Jamshidi P, Pera M, Pebay A (2007) Anti-apoptotic effect of sphingosine-1-phosphate and platelet-derived growth factor in human embryonic stem cells. Stem Cells Dev 16:989–1001PubMedCrossRefGoogle Scholar
  70. 70.
    Arboleda G, Morales LC, Benitez B, Arboleda H (2009) Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration. Brain Res Rev 59:333–346PubMedCrossRefGoogle Scholar
  71. 71.
    Bourbon NA, Sandirasegarane L, Kester M (2002) Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem 277:3286–3292PubMedCrossRefGoogle Scholar
  72. 72.
    Stoica BA, Movsesyan VA, Lea PM 4th, Faden AI (2003) Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 22:365–382PubMedCrossRefGoogle Scholar
  73. 73.
    Osawa Y, Uchinami H, Bielawski J, Schwabe RF, Hannun YA, Brenner DA (2005) Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J Biol Chem 280:27879–27887PubMedCrossRefGoogle Scholar
  74. 74.
    Fernandez-Marcos PJ, Abu-Baker S, Joshi J, Galvez A, Castilla EA, Canamero M, Collado M, Saez C, Moreno-Bueno G, Palacios J, Leitges M, Serrano M, Moscat J and Diaz-Meco MT (2009) Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-{kappa}B activation and invasive prostate carcinoma. Proc Natl Acad Sci USAGoogle Scholar
  75. 75.
    Lee TJ, Lee JT, Kim SH, Choi YH, Song KS, Park JW, Kwon TK (2008) Overexpression of Par-4 enhances thapsigargin-induced apoptosis via down-regulation of XIAP and inactivation of Akt in human renal cancer cells. J Cell Biochem 103:358–368PubMedCrossRefGoogle Scholar
  76. 76.
    Diaz-Meco MT, Abu-Baker S (2009) The Par-4/PTEN connection in tumor suppression. Cell Cycle 8:2518–2522PubMedCrossRefGoogle Scholar
  77. 77.
    Lee TJ, Jang JH, Noh HJ, Park EJ, Choi KS, Kwon TK (2010) Overexpression of Par-4 sensitizes TRAIL-induced apoptosis via inactivation of NF-kappaB and Akt signaling pathways in renal cancer cells. J Cell Biochem 109:885–895PubMedGoogle Scholar
  78. 78.
    Sun B, Lu C, Zhou GP, Xing CY (2010) Suppression of Par-4 protects human renal proximal tubule cells from apoptosis induced by oxidative stress. Nephron Exp Nephrol 117:e53–e61CrossRefGoogle Scholar
  79. 79.
    Goswami A, Ranganathan P, Rangnekar VM (2006) The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Res 66:2889–2892PubMedCrossRefGoogle Scholar
  80. 80.
    Hancock CR, Wetherington JP, Lambert NA, Condie BG (2000) Neuronal differentiation of cryopreserved neural progenitor cells derived from mouse embryonic stem cells. Biochem Biophys Res Commun 271:418–421PubMedCrossRefGoogle Scholar
  81. 81.
    Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD (1996) Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59:89–102PubMedCrossRefGoogle Scholar
  82. 82.
    Ruhparwar A, Bara C, Kofidis T, Ruebesamen N, Karck M, Martin U, Haverich A (2006) In vivo detection of integration of grafted cells after myocardial transplantation. Zentralbl Chir 131:420–424PubMedCrossRefGoogle Scholar
  83. 83.
    Ruhparwar A, Kofidis T, Ruebesamen N, Karck M, Haverich A, Martin U (2005) Intra-vital fluorescence microscopy for intra-myocardial graft detection following cell transplantation. Int J Cardiovasc Imaging 21:569–574PubMedCrossRefGoogle Scholar
  84. 84.
    Xian HQ, McNichols E, St Clair A, Gottlieb DI (2003) A subset of ES-cell-derived neural cells marked by gene targeting. Stem Cells 21:41–49PubMedCrossRefGoogle Scholar
  85. 85.
    Xian H, Gottlieb DI (2004) Dividing Olig2-expressing progenitor cells derived from ES cells. Glia 47:88–101PubMedCrossRefGoogle Scholar
  86. 86.
    Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003) The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 554:189–193PubMedCrossRefGoogle Scholar
  87. 87.
    Loveridge C, Tonelli F, Leclercq T, Lim KG, Long JS, Berdyshev E, Tate RJ, Natarajan V, Pitson SM, Pyne NJ, Pyne S (2010) The sphingosine kinase 1 inhibitor 2-(P-hydroxyanilino)-4-(P-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. J Biol Chem. doi: 10.1074/jbc.M110.127993
  88. 88.
    Berdyshev EV, Gorshkova I, Skobeleva A, Bittman R, Lu X, Dudek SM, Mirzapoiazova T, Garcia JG, Natarajan V (2009) FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. J Biol Chem 284:5467–5477PubMedCrossRefGoogle Scholar
  89. 89.
    Tonelli F, Lim KG, Loveridge C, Long J, Pitson SM, Tigyi G, Bittman R, Pyne S, Pyne NJ (2010) FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells. Cell Signal 22:1536–1542PubMedCrossRefGoogle Scholar
  90. 90.
    Lahiri S, Park H, Laviad EL, Lu X, Bittman R, Futerman AH (2009) Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-de pend ent manner. J Biol Chem 284:16090–16098PubMedCrossRefGoogle Scholar
  91. 91.
    Kasai N, Yu RK (1983) The monoclonal antibody A2B5 is specific to ganglioside GQ1c. Brain Res 277:155–158PubMedCrossRefGoogle Scholar
  92. 92.
    Kim SU, Moretto G, Lee V, Yu RK (1986) Neuroimmunology of gangliosides in human neurons and glial cells in culture. J Neurosci Res 15:303–321PubMedCrossRefGoogle Scholar
  93. 93.
    Rao MS, Mayer-Proschel M (1997) Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol 188:48–63PubMedCrossRefGoogle Scholar
  94. 94.
    Rao MS, Noble M, Mayer-Proschel M (1998) A tripotential glial precursor cell is present in the developing spinal cord. Proc Natl Acad Sci USA 95:3996–4001PubMedCrossRefGoogle Scholar
  95. 95.
    Herrera J, Yang H, Zhang SC, Proschel C, Tresco P, Duncan ID, Luskin M, Mayer-Proschel M (2001) Embryonic-derived glial-restricted precursor cells (GRP cells) can differentiate into astrocytes and oligodendrocytes in vivo. Exp Neurol 171:11–21PubMedCrossRefGoogle Scholar
  96. 96.
    Noble M, Proschel C, Mayer-Proschel M (2004) Getting a GR(i)P on oligodendrocyte development. Dev Biol 265:33–52PubMedCrossRefGoogle Scholar
  97. 97.
    Levi G, Gallo V, Ciotti MT (1986) Bipotential precursors of putative fibrous astrocytes and oligodendrocytes in rat cerebellar cultures express distinct surface features and “neuron-like” gamma-aminobutyric acid transport. Proc Natl Acad Sci USA 83:1504–1508PubMedCrossRefGoogle Scholar
  98. 98.
    Schnitzer J, Schachner M (1982) Cell type specificity of a neural cell surface antigen recognized by the monoclonal antibody A2B5. Cell Tissue Res 224:625–636PubMedCrossRefGoogle Scholar
  99. 99.
    Abney ER, Williams BP, Raff MC (1983) Tracing the development of oligodendrocytes from precursor cells using monoclonal antibodies, fluorescence-activated cell sorting, and cell culture. Dev Biol 100:166–171PubMedCrossRefGoogle Scholar
  100. 100.
    Raff MC, Abney ER, Miller RH (1984) Two glial cell lineages diverge prenatally in rat optic nerve. Dev Biol 106:53–60PubMedCrossRefGoogle Scholar
  101. 101.
    Saneto RP, de Vellis J (1985) Characterization of cultured rat oligodendrocytes proliferating in a serum-free, chemically defined medium. Proc Natl Acad Sci USA 82:3509–3513PubMedCrossRefGoogle Scholar
  102. 102.
    Lubetzki C, Goujet-Zalc C, Gansmuller A, Monge M, Brillat A, Zalc B (1991) Morphological, biochemical, and functional characterization of bulk isolated glial progenitor cells. J Neurochem 56:671–680PubMedCrossRefGoogle Scholar
  103. 103.
    Kalyani A, Hobson K, Rao MS (1997) Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis. Dev Biol 186:202–223PubMedCrossRefGoogle Scholar
  104. 104.
    Amat JA, Farooq M, Ishiguro H, Norton WT (1998) Cells of the oligodendrocyte lineage proliferate following cortical stab wounds: an in vitro analysis. Glia 22:64–71PubMedCrossRefGoogle Scholar
  105. 105.
    Bansal R, Winkler S, Bheddah S (1999) Negative regulation of oligodendrocyte differentiation by galactosphingolipids. J Neurosci 19:7913–7924PubMedGoogle Scholar
  106. 106.
    Gensert JM, Goldman JE (2001) Heterogeneity of cycling glial progenitors in the adult mammalian cortex and white matter. J Neurobiol 48:75–86PubMedCrossRefGoogle Scholar
  107. 107.
    Wilson HC, Onischke C, Raine CS (2003) Human oligodendrocyte precursor cells in vitro: phenotypic analysis and differential response to growth factors. Glia 44:153–165PubMedCrossRefGoogle Scholar
  108. 108.
    Dasgupta S, Everhart MB, Bhat NR, Hogan EL (1997) Neutral monoglycosylceramides in rat brain: occurrence, molecular expression and developmental variation. Dev Neurosci 19:152–161PubMedCrossRefGoogle Scholar
  109. 109.
    Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, Crist SA, Humphreys S, Rangnekar VM (1994) Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ 5:457–466PubMedGoogle Scholar
  110. 110.
    Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4:957–962PubMedCrossRefGoogle Scholar
  111. 111.
    Azmi AS, Wang Z, Burikhanov R, Rangnekar VM, Wang G, Chen J, Wang S, Sarkar FH, Mohammad RM (2008) Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis. Mol Cancer Ther 7:2884–2893PubMedCrossRefGoogle Scholar
  112. 112.
    Zhao Y, Rangnekar VM (2008) Apoptosis and tumor resistance conferred by Par-4. Cancer Biol Ther 7:1867–1874PubMedCrossRefGoogle Scholar
  113. 113.
    Wang G, Silva J, Krishnamurthy K, Bieberich E (2006) A novel isoform of prostate apoptosis response 4 (PAR-4) that co-distributes with F-actin and prevents apoptosis in neural stem cells. Apoptosis 11:315–325PubMedCrossRefGoogle Scholar
  114. 114.
    Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4:397–407PubMedCrossRefGoogle Scholar
  115. 115.
    Sim-Selley LJ, Goforth PB, Mba MU, Macdonald TL, Lynch KR, Milstien S, Spiegel S, Satin LS, Welch SP, Selley DE (2009) Sphingosine-1-phosphate receptors mediate neuromodulatory functions in the CNS. J Neurochem 110:1191–1202PubMedCrossRefGoogle Scholar
  116. 116.
    Taha TA, Argraves KM, Obeid LM (2004) Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochim Biophys Acta 1682:48–55PubMedGoogle Scholar
  117. 117.
    Mao C, Obeid LM (2008) Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta 1781:424–434PubMedGoogle Scholar
  118. 118.
    Qin J, Berdyshev E, Goya J, Natarajan V, Dawson G (2010) Neurons and oligodendrocytes recycle sphingosine 1-phosphate to ceramide: significance for apoptosis and multiple sclerosis. J Biol Chem 285:14134–14143PubMedCrossRefGoogle Scholar
  119. 119.
    Coelho RP, Saini HS, Sato-Bigbee C (2010) Sphingosine-1-phosphate and oligodendrocytes: from cell development to the treatment of multiple sclerosis. Prostaglandins Other Lipid Mediat 91:139–144PubMedCrossRefGoogle Scholar
  120. 120.
    Miron VE, Jung CG, Kim HJ, Kennedy TE, Soliven B, Antel JP (2008) FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 63:61–71PubMedCrossRefGoogle Scholar
  121. 121.
    Miron VE, Schubart A, Antel JP (2008) Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 274:13–17PubMedCrossRefGoogle Scholar
  122. 122.
    Lee CW, Choi JW, Chun J (2010) Neurological S1P signaling as an emerging mechanism of action of oral FTY720 (Fingolimod) in multiple sclerosis. Arch Pharm Res 33:1567–1574PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Program in Developmental Neurobiology, Institute of Molecular Medicine and Genetics, School of MedicineMedical College of Georgia/Georgia Health Sciences UniversityAugustaUSA

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