The application of human pluripotent stem cells to model the neuronal and glial components of neurodevelopmental disorders

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Abstract

Cellular models of neurodevelopmental disorders provide a valuable experimental system to uncover disease mechanisms and novel therapeutic strategies. The ability of induced pluripotent stem cells (iPSCs) to generate diverse brain cell types offers great potential to model several neurodevelopmental disorders. Further patient-derived iPSCs have the unique genetic and molecular signature of the affected individuals, which allows researchers to address limitations of transgenic behavioural models, as well as generate hypothesis-driven models to study disorder-relevant phenotypes at a cellular level. In this article, we review the extant literature that has used iPSC-based modelling to understand the neuronal and glial contributions to neurodevelopmental disorders including autism spectrum disorder (ASD), Rett syndrome, bipolar disorder (BP), and schizophrenia. For instance, several molecular candidates have been shown to influence cellular phenotypes in three-dimensional iPSC-based models of ASD patients. Delays in differentiation of astrocytes and morphological changes of neurons are associated with Rett syndrome. In the case of bipolar disorders and schizophrenia, patient-derived models helped to identify cellular phenotypes associated with neuronal deficits (e.g., excitability) and mutation-specific abnormalities in oligodendrocytes (e.g., CSPG4). Further we provide a critical review of the current limitations of this field and provide methodological suggestions to enhance future modelling efforts of neurodevelopmental disorders. Future developments in experimental design and methodology of disease modelling represent an exciting new avenue relevant to neurodevelopmental disorders.

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References

  1. 1.

    Gratten J, Wray NR, Keller MC, Visscher PM. Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci. 2014;17:782–90.

  2. 2.

    Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X, et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry. 2015;20:1350–65.

  3. 3.

    Sloan SA, Barres BA. Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr Opin Neurobiol. 2014;27:75–81.

  4. 4.

    Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L, et al. Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. Cell Stem Cell. 2017;21:195–208.e6.

  5. 5.

    Ardhanareeswaran K, Mariani J, Coppola G, Abyzov A, Vaccarino FM. Human induced pluripotent stem cells for modelling neurodevelopmental disorders. Nat Rev Neurol. 2017;13:265–78.

  6. 6.

    Soliman MA, Aboharb F, Zeltner N, Studer L. Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry. 2017;22:1241–9.

  7. 7.

    O’Shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: IPSC models. Mol Cell Neurosci. 2016;73:63–83.

  8. 8.

    Gao Y, Galante M, El-Mallakh J, Nurnberger JI, Delamere NA, Lei Z, et al. BDNF expression in lymphoblastoid cell lines carrying BDNF SNPs associated with bipolar disorder. Psychiatry Genet. 2012;22:253–5.

  9. 9.

    Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci. 2009;3:31.

  10. 10.

    Piven J, Palmer P, Jacobi D, Childress D, Arndt S. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry. 1997;154:185–90.

  11. 11.

    Ronald A, Happé F, Bolton P, Butcher LM, Price TS, Wheelwright S, et al. Genetic heterogeneity between the three components of the autism spectrum: A twin study. J Am Acad Child Adolesc Psychiatry. 2006;45:691–9.

  12. 12.

    Won H, Mah W, Kim E. Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci. 2013;6:19.

  13. 13.

    Mariani J, Vittoria M, Palejev D, Tomasini Livia, Coppola G, Szekely AM, et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci USA. 2012;109:12770–5.

  14. 14.

    Russo FB, Freitas BC, Pignatari GC, Fernandes IR, Sebat J, Muotri AR, et al. Modeling the Interplay Between Neurons and Astrocytes in Autism Using Human Induced Pluripotent Stem Cells. Biol Psychiatry. 2018;83:569–78.

  15. 15.

    Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998;85:106–9.

  16. 16.

    Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, et al. Microglial Activation in Young Adults With Autism Spectrum Disorder. JAMA. Psychiatry. 2013;70:49.

  17. 17.

    Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67–81.

  18. 18.

    Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell. 2015;162:375–90.

  19. 19.

    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.

  20. 20.

    Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci. 2013;16:898–902.

  21. 21.

    Cohen DR, Matarazzo V, Palmer AM, Tu Y, Jeon O-H, Pevsner J, et al. Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol Cell Neurosci. 2003;22:417–29.

  22. 22.

    Zhou Z, Hong EJ, Cohen S, Zhao W, Ho HH, Schmidt L, et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52:255–69.

  23. 23.

    Marchetto MCN, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, et al. A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells. Cell. 2010;143:527–39.

  24. 24.

    Andoh-Noda T, Akamatsu W, Miyake K, Matsumoto T, Yamaguchi R, Sanosaka T, et al. Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage. Mol Brain. 2015;8:1–11.

  25. 25.

    Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q. et al. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild- type neurons. Hum Mol Genet. 2014;23:2968–80.

  26. 26.

    Dusetzina SB, Farley JF, Weinberger M, Gaynes BN, Sleath B, Hansen RA. Treatment use and costs among privately insured youths with diagnoses of bipolar disorder. Psychiatr Serv. 2012;63:1019–25.

  27. 27.

    Benes FM, Vincent SL, Todtenkopf M. The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biol Psychiatry. 2001;50:395–406.

  28. 28.

    Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58:545–53.

  29. 29.

    Gittins RA, Harrison PJ. A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord. 2011;133:328–32.

  30. 30.

    Gos T, Schroeter ML, Lessel W, Bernstein HG, Dobrowolny H, Schiltz K, et al. S100B-immunopositive astrocytes and oligodendrocytes in the hippocampus are differentially afflicted in unipolar and bipolar depression: a postmortem study. J Psychiatr Res. 2013;47:1694–9.

  31. 31.

    Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res. 2004;67:269–75.

  32. 32.

    Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry. 2003;53:906–13.

  33. 33.

    Deicken RF, Pegues MP, Anzalone S, Feiwell R, Soher B. Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder. Am J Psychiatry. 2003;160:873–82.

  34. 34.

    Mertens J, Wang Q, Kim Y, Yu DX, Pham S, Yang B, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–9.

  35. 35.

    Madison J, Zhou F, Nigam A, Hussain A, Barker D, Nehme R, et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry. 2015;20:703–17.

  36. 36.

    Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a Complex Trait. Arch Gen Psychiatry. 2003;60:1187.

  37. 37.

    Wong AHC, Van Tol HHM. Schizophrenia: from phenomenology to neurobiology. Neurosci Biobehav Rev. 2003;27:269–306.

  38. 38.

    Javitt DC. Glycine transport inhibitors and the treatment of schizophrenia. Biol Psychiatry. 2008;63:6–8.

  39. 39.

    Rubinov M, Bullmore E. Schizophrenia and abnormal brain network hubs. Dialog Clin Neurosci. 2013;15:339–49.

  40. 40.

    Federspiel A, Begré S, Kiefer C, Schroth G, Strik WK, Dierks T. Alterations of white matter connectivity in first episode schizophrenia. Neurobiol Dis. 2006;22:702–9.

  41. 41.

    Begré S, Koenig T. Cerebral disconnectivity: An early event in schizophrenia. Neuroscientist. 2008;14:19–45.

  42. 42.

    Bernstein SL, Dupuis NF, Lazo ND, Wyttenbach T, Condron MM, Bitan G. et al. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat Chem. 2009;1:326–31.

  43. 43.

    Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC. Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res. 2007;151:179–88.

  44. 44.

    Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–5.

  45. 45.

    Robicsek O, Karry R, Petit I, Salman-Kesner N, Müller F-J, Klein E, et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry. 2013;18:1067–76.

  46. 46.

    Chiang CH, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL, et al. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry. 2011;16:358–60.

  47. 47.

    Clarke LE, Barres BA. Glia keep synapse distribution under wraps. Cell. 2013;154:267–8.

  48. 48.

    de Vrij FM, Bouwkamp CG, Gunhanlar N, Shpak G, Lendemeijer B, Baghdadi M et al. Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia. Mol Psychiatry 2018;24:757–71.

  49. 49.

    Katsel P, Davis KL, Gorman JM, Haroutunian V. Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr Res. 2005;77:241–52.

  50. 50.

    Bauer D, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE. Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res. 2010;117:92–8.

  51. 51.

    Inoue H, Yamanaka S. The use of induced pluripotent stem cells in drug development. Clin Pharmcol Ther. 2011;89:655–61.

  52. 52.

    Hadida S, Van Goor F, Zhou J, Arumugam V, McCartney J, Hazlewood A, et al. Discovery of N -(2,4-Di- tert -butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem. 2014;57:9776–95.

  53. 53.

    Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SSW, Sandoe J, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014;7:1–11.

  54. 54.

    Haggarty SJ, Silva MC, Cross A, Brandon NJ, Perlis RH. Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models. Mol Cell Neurosci. 2016;73:104–15.

  55. 55.

    Kimbrel EA, Robert L. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov. 2015;14:681–92.

  56. 56.

    Doi D, Samata B, Katsukawa M, Kikuchi T, Morizane A, Ono Y, et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Rep. 2014;2:337–50.

  57. 57.

    Kirkeby A, Grealish S, Wolf DA, Nelander J, Wood J, Lundblad M, et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012;1:703–14.

  58. 58.

    Kriks S, Shim J-W, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480:547–51.

  59. 59.

    Hemmer K, Zhang M, Van Wüllen T, Sakalem M, Tapia N, Baumuratov A, et al. Induced neural stem cells achieve long-term survival and functional integration in the adult mouse brain. Stem Cell Rep. 2014;3:423–31.

  60. 60.

    Johnson MA, Weick JP, Pearce RA, Zhang S. Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci. 2007;27:3069–77.

  61. 61.

    Ilieva M, Fex Svenningsen Å, Thorsen M, Michel TM. Psychiatry in a dish: stem cells and brain organoids modeling autism spectrum disorders. Biol Psychiatry. 2018;83:558–68.

  62. 62.

    Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell. 2008;3:519–32.

  63. 63.

    Edmondson R, Broglie JJ, Adcock AF, Yang L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol. 2014;12:207–18.

  64. 64.

    Baharvand H, Hashemi SM, Ashtiani SK, Farrokhi A. Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol. 2006;50:645–52.

  65. 65.

    Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature. 2011;473:92–6.

  66. 66.

    Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell. 2011;8:106–18.

  67. 67.

    Pera MF. The dark side of induced pluripotency. Nature. 2011;471:46–7.

  68. 68.

    Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY.et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010;28:848–55.

  69. 69.

    Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285–90.

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Acknowledgements

We acknowledge the financial support of the National Health and Medical Research Council (NHMRC) [Early Career Fellowship ID 1112452 (JT)], the Society for Mental Health Research [Early Career Research Project Grant Award (JT)], the Rebecca L Cooper Medical Research Foundation [Medical Research Grant ID 10409 (JT)] and Monash University [Strategic Grant Scheme ID SGS16-0410 (JT)]. MAB is supported by a Senior Research Fellowship from the NHMRC (APP1154378). MAB, JT, and ZH are supported by project funding from the NHMRC (APP1146644).

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Correspondence to J. Tong.

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