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Human Embryonic Stem Cell-Derived Neurons as a Tool for Studying Neuroprotection and Neurodegeneration

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Abstract

The capacity to generate myriad differentiated cell types, including neurons, from human embryonic stem (hES) cell lines offers great potential for developing cell-based therapies and also for increasing our understanding of human developmental mechanisms. In addition, the emerging development of this technology as an experimental tool represents a potential opportunity for neuroscientists interested in mechanisms of neuroprotection and neurodegeneration. Potentially unlimited generation of well-defined functional neurons from hES and patient-specific induced pluripotent cells offers new systems to study disease mechanisms, signalling pathways and receptor pharmacology within a human cellular environment. Such systems may help in overcoming interspecies differences. Far from replacing rodent in vivo and primary culture systems, hES and induced disease-specific pluripotent stem cell-derived neurons offer a complementary resource to overcome issues of interspecies differences, accelerate drug discovery, study of disease mechanism and provide basic insight into human neuronal physiology.

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References

  1. Hoffman LM, Carpenter MK (2005) Characterization and culture of human embryonic stem cells. Nat Biotechnol 23(6):699–708

    Article  CAS  PubMed  Google Scholar 

  2. Dhara SK, Stice SL (2008) Neural differentiation of human embryonic stem cells. J Cell Biochem 105(3):633–640

    Article  CAS  PubMed  Google Scholar 

  3. Murry CE, Keller G (2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132(4):661–680

    Article  CAS  PubMed  Google Scholar 

  4. Zeng X, Chen J, Deng X, Liu Y, Rao MS, Cadet JL, Freed WJ (2006) An in vitro model of human dopaminergic neurons derived from embryonic stem cells: MPP+ toxicity and GDNF neuroprotection. Neuropsychopharmacology 31(12):2708–2715

    Article  CAS  PubMed  Google Scholar 

  5. Krencik R, Zhang SC (2006) Stem cell neural differentiation: a model for chemical biology. Curr Opin Chem Biol 10(6):592–597

    Article  CAS  PubMed  Google Scholar 

  6. Smith JR, Vallier L, Lupo G, Alexander M, Harris WA, Pedersen RA (2008) Inhibition of Activin/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev Biol 313(1):107–117

    Article  CAS  PubMed  Google Scholar 

  7. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275–280

    Article  CAS  PubMed  Google Scholar 

  8. Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A (2005) Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3(9):e283

    Article  PubMed  Google Scholar 

  9. Joannides AJ, Fiore-Heriche C, Battersby AA, Athauda-Arachchi P, Bouhon IA, Williams L, Westmore K, Kemp PJ, Compston A, Allen ND, Chandran S (2007) A scaleable and defined system for generating neural stem cells from human embryonic stem cells. Stem Cells 25(3):731–737

    Article  CAS  PubMed  Google Scholar 

  10. Pankratz MT, Li XJ, Lavaute TM, Lyons EA, Chen X, Zhang SC (2007) Directed neural differentiation of human embryonic stem cells via an obligated primitive anterior stage. Stem Cells 25(6):1511–1520

    Article  CAS  PubMed  Google Scholar 

  11. Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S, Kawasaki H, Watanabe Y, Mizuseki K, Sasai Y (2005) Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 8(3):288–296

    Article  CAS  PubMed  Google Scholar 

  12. Patani R, Compston DA, Puddifoot C, Wyllie DJ, Hardingham GE, Allen ND, Chandran S (2009) Activin/Nodal inhibition alone accelerates highly efficient neural conversion from human embryonic stem cells and imposes a caudal positional identity. PLoS ONE, In press

  13. Yan Y, Yang D, Zarnowska ED, Du Z, Werbel B, Valliere C, Pearce RA, Thomson JA, Zhang SC (2005) Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23(6):781–790

    Article  CAS  PubMed  Google Scholar 

  14. Shin S, Dalton S, Stice SL (2005) Human motor neuron differentiation from human embryonic stem cells. Stem Cells Dev 14(3):266–269

    Article  CAS  PubMed  Google Scholar 

  15. Li XJ, Hu BY, Jones SA, Zhang YS, Lavaute T, Du ZW, Zhang SC (2008) Directed differentiation of ventral spinal progenitors and motor neurons from human embryonic stem cells by small molecules. Stem Cells 26(4):886–893

    Article  CAS  PubMed  Google Scholar 

  16. Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL (2008) Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A 105(43):16707–16712

    Article  CAS  PubMed  Google Scholar 

  17. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN (2009) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457(7227):277–280

    Article  CAS  PubMed  Google Scholar 

  18. Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461(7262):402–406

    Article  CAS  PubMed  Google Scholar 

  19. Cezar GG (2007) Can human embryonic stem cells contribute to the discovery of safer and more effective drugs? Curr Opin Chem Biol 11(4):405–409

    Article  CAS  PubMed  Google Scholar 

  20. Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305

    Article  CAS  PubMed  Google Scholar 

  21. Papadia S (2007) and G.E. Hardingham, The dichotomy of NMDA receptor signaling. Neuroscientist 13:572–579

    Article  CAS  PubMed  Google Scholar 

  22. Dermitzakis ET, Clark AG (2002) Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover. Mol Biol Evol 19(7):1114–1121

    CAS  PubMed  Google Scholar 

  23. Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA, Conboy CM, Gifford DK, Fraenkel E (2007) Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat Genet 39(6):730–732

    Article  CAS  PubMed  Google Scholar 

  24. Wilson MD, Barbosa-Morais NL, Schmidt D, Conboy CM, Vanes L, Tybulewicz VL, Fisher EM, Tavare S, Odom DT (2008) Species-specific transcription in mice carrying human chromosome 21. Science 322(5900):434–438

    Article  CAS  PubMed  Google Scholar 

  25. Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner BA, Wyllie DJ, Ikonomidou C, Hardingham GE (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11(4):476–487

    Article  CAS  PubMed  Google Scholar 

  26. Roy SW, Gilbert W (2006) The evolution of spliceosomal introns: patterns, puzzles and progress. Nat Rev Genet 7(3):211–221

    PubMed  Google Scholar 

  27. Laurell H, Grober J, Vindis C, Lacombe T, Dauzats M, Holm C, Langin D (1997) Species-specific alternative splicing generates a catalytically inactive form of human hormone-sensitive lipase. Biochem J 328(Pt 1):137–143

    CAS  PubMed  Google Scholar 

  28. McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L, Leverenz J, Schellenberg GD, D'Souza I (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol 511(6):788–803

    Article  CAS  PubMed  Google Scholar 

  29. Van Eylen F, Bollen A, Herchuelz A (2001) 2001. J Endocrinol 168(3):517–526

    Article  PubMed  Google Scholar 

  30. Bano D, Nicotera P (2007) Ca2+ signals and neuronal death in brain ischemia. Stroke 38(2 Suppl):674–676

    Article  CAS  PubMed  Google Scholar 

  31. Liew CW, Vockel M, Glassmeier G, Brandner JM, Fernandez-Ballester GJ, Schwarz JR, Schulz S, Buck F, Serrano L, Richter D, Kreienkamp HJ (2009) Interaction of the human somatostatin receptor 3 with the multiple PDZ domain protein MUPP1 enables somatostatin to control permeability of epithelial tight junctions. FEBS Lett 583(1):49–54

    Article  CAS  PubMed  Google Scholar 

  32. Kim E, Sheng M (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5(10):771–781

    Article  CAS  PubMed  Google Scholar 

  33. Collins MO, Grant SG (2007) Supramolecular signalling complexes in the nervous system. Subcell Biochem 43:185–207

    Article  CAS  PubMed  Google Scholar 

  34. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW, Tymianski M (2002) Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 298(5594):846–850

    Article  CAS  PubMed  Google Scholar 

  35. Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ (2005) The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol 168(1):117–126

    Article  CAS  PubMed  Google Scholar 

  36. Soriano FX, Martel MA, Papadia S, Vaslin A, Baxter P, Rickman C, Forder J, Tymianski M, Duncan R, Aarts M, Clarke P, Wyllie DJ, Hardingham GE (2008) Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J Neurosci 28(42):10696–10710

    Article  CAS  PubMed  Google Scholar 

  37. Meier P, Vousden KH (2007) Lucifer's labyrinth--ten years of path finding in cell death. Mol Cell 28(5):746–754

    Article  CAS  PubMed  Google Scholar 

  38. Viswanath V, Wu Y, Boonplueang R, Chen S, Stevenson FF, Yantiri F, Yang L, Beal MF, Andersen JK (2001) Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. J Neurosci 21(24):9519–9528

    CAS  PubMed  Google Scholar 

  39. Mattson MP (2006) Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 8(11–12):1997–2006

    CAS  PubMed  Google Scholar 

  40. Ribe EM, Serrano-Saiz E, Akpan N, Troy CM (2008) Mechanisms of neuronal death in disease: defining the models and the players. Biochem J 415(2):165–182

    Article  CAS  PubMed  Google Scholar 

  41. Rohn TT, Head E (2009) Caspases as therapeutic targets in Alzheimer's disease: is it time to “cut” to the chase? Int J Clin Exp Pathol 2(2):108–118

    CAS  PubMed  Google Scholar 

  42. Ussat S, Werner U, Adam-Klages S (2002) Species-specific differences in the usage of several caspase substrates. Biochem Biophys Res Commun 297(5):1186–1190

    Article  CAS  PubMed  Google Scholar 

  43. Tittle RK, Hume RI (2008) Opposite effects of zinc on human and rat P2X2 receptors. J Neurosci 28(44):11131–11140

    Article  CAS  PubMed  Google Scholar 

  44. Phillips E, Reeve A, Bevan S, McIntyre P (2004) Identification of species-specific determinants of the action of the antagonist capsazepine and the agonist PPAHV on TRPV1. J Biol Chem 279(17):17165–17172

    Article  CAS  PubMed  Google Scholar 

  45. Klionsky L, Tamir R, Gao B, Wang W, Immke DC, Nishimura N, Gavva NR (2007) Species-specific pharmacology of trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists. Mol Pain 3:39

    Article  PubMed  Google Scholar 

  46. Gilling KE, Jatzke C, Hechenberger M, Parsons CG (2009) Potency, voltage-dependency, agonist concentration-dependency, blocking kinetics and partial untrapping of the uncompetitive N-methyl-d-aspartate (NMDA) channel blocker memantine at human NMDA (GluN1/GluN2A) receptors. Neuropharmacology 56(5):866–875

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK

    Giles E. Hardingham, Paul Baxter & David J. Wyllie

  2. Laboratory for Regenerative Medicine & Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Rickie Patani

  3. The Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK

    Giles E. Hardingham & Siddharthan Chandran

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  1. Giles E. Hardingham
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  2. Rickie Patani
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  4. David J. Wyllie
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  5. Siddharthan Chandran
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Corresponding authors

Correspondence to Giles E. Hardingham or Siddharthan Chandran.

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Hardingham, G.E., Patani, R., Baxter, P. et al. Human Embryonic Stem Cell-Derived Neurons as a Tool for Studying Neuroprotection and Neurodegeneration. Mol Neurobiol 42, 97–102 (2010). https://doi.org/10.1007/s12035-010-8136-2

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  • DOI: https://doi.org/10.1007/s12035-010-8136-2

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