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Modelling neurodegenerative diseases in vitro: Recent advances in 3D iPSC technologies

1 WISH laboratories, University Hospital Southampton, Southampton, UK
2 Centre for Biological Sciences, University of Southampton, Southampton, UK
3 Clinical Neurosciences, Faculty of Medicine and Centre for Human Development, Stem Cells and regenerative Medicine, University of Southampton, Southampton, UK

Special Issues: iPS Cell Technologies in Human Diseases

The discovery of induced pluripotent stem cells (iPSC) 12 years ago has fostered the development of innovative patient-derived in vitro models for better understanding of disease mechanisms. This is particularly relevant to neurodegenerative diseases, where availability of live human brain tissue for research is limited and post-mortem interval changes influence readouts from autopsy-derived human tissue. Hundreds of iPSC lines have now been prepared and banked, thanks to several large scale initiatives and cell banks. Patient- or engineered iPSC-derived neural models are now being used to recapitulate cellular and molecular aspects of a variety of neurodegenerative diseases, including early and pre-clinical disease stages. The broad relevance of these models derives from the availability of a variety of differentiation protocols to generate disease-specific cell types and the manipulation to either introduce or correct disease-relevant genetic modifications. Moreover, the use of chemical and physical three-dimensional (3D) matrices improves control over the extracellular environment and cellular organization of the models. These iPSC-derived neural models can be utilised to identify target proteins and, importantly, provide high-throughput screening for drug discovery. Choosing Alzheimer’s disease (AD) as an example, this review describes 3D iPSC-derived neural models and their advantages and limitations. There is now a requirement to fully characterise and validate these 3D iPSC-derived neural models as a viable research tool that is capable of complementing animal models of neurodegeneration and live human brain tissue. With further optimization of differentiation, maturation and aging protocols, as well as the 3D cellular organisation and extracellular matrix to recapitulate more closely, the molecular extracellular-environment of the human brain, 3D iPSC-derived models have the potential to deliver new knowledge, enable discovery of novel disease mechanisms and identify new therapeutic targets for neurodegenerative diseases.
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1. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676.    

2. Okita K, Nakagawa M, Hyenjong H, et al. (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322: 949–953.    

3. Yu J, Hu K, Smuga-Otto K, et al. (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324: 797–801.    

4. Stadtfeld M, Nagaya M, Utikal J, et al. (2008) Induced pluripotent stem cells generated without viral integration. Science 322: 945–949.    

5. Okita K, Matsumura Y, Sato Y, et al. (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8: 409–412.    

6. Nussbaum J, Minami E, Laflamme MA, et al. (2007) Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. Faseb J 21: 1345–1357.    

7. Swijnenburg RJ, Schrepfer S, Cao F, et al. (2008) In vivo imaging of embryonic stem cells reveals patterns of survival and immune rejection following transplantation. Stem Cells Dev 17: 1023–1029.    

8. Burkhardt MF, Martinez FJ, Wright S, et al. (2013) A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells. Mol Cell Neurosci 56: 355–364.    

9. Zhang Y, Schmid B, Nikolaisen NK, et al. (2017) Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B. Stem Cell Reports 8: 648–658.    

10. Du X, Parent JM (2015) Using Patient-Derived Induced Pluripotent Stem Cells to Model and Treat Epilepsies. Curr Neurol Neurosci Rep 15: 71.    

11. Chambers SM, Fasano CA, Papapetrou EP, et al. (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27: 275–280.    

12. Shi Y, Kirwan P, Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7: 1836–1846.    

13. Li W, Sun W, Zhang Y, et al. (2011) Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc Natl Acad Sci U S A 108: 8299–8304.    

14. De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer's Disease. Cell 164: 603–615.    

15. Windrem MS, Osipovitch M, Liu Z, et al. (2017) Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. Cell Stem Cell 21: 195–208.    

16. Serio A, Bilican B, Barmada SJ, et al. (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A 110: 4697–4702.    

17. Hall CE, Yao Z, Choi M, et al. (2017) Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. Cell Rep 19: 1739–1749.    

18. Madill M, McDonagh K, Ma J, et al. (2017) Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms. Mol Brain 10: 22.    

19. Hallmann AL, Arauzo-Bravo MJ, Mavrommatis L, et al. (2017) Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein. Sci Rep 7: 42991.    

20. Oksanen M, Petersen AJ, Naumenko N, et al. (2017) PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. Stem Cell Reports 9: 1885–1897.    

21. Kaufmann M, Schuffenhauer A, Fruh I, et al. (2015) High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome. J Biomol Screen 20: 1101–1111.    

22. Hu BY, Weick JP, Yu J, et al. (2010) Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci U S A 107: 4335–4340.    

23. Johnson MA, Weick JP, Pearce RA, et al. (2007) Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. J Neurosci 27: 3069–3077.    

24. Adil MM, Rodrigues GM, Kulkarni RU, et al. (2017) Efficient generation of hPSC-derived midbrain dopaminergic neurons in a fully defined, scalable, 3D biomaterial platform. Sci Rep 7: 40573.    

25. Hartfield EM, Yamasaki-Mann M, Ribeiro Fernandes HJ, et al. (2014) Physiological characterisation of human iPS-derived dopaminergic neurons. PLoS One 9: e87388.    

26. Song M, Mohamad O, Chen D, et al. (2013) Coordinated development of voltage-gated Na+ and K+ currents regulates functional maturation of forebrain neurons derived from human induced pluripotent stem cells. Stem Cells Dev 22: 1551–1563.    

27. Koehler KR, Tropel P, Theile JW, et al. (2011) Extended passaging increases the efficiency of neural differentiation from induced pluripotent stem cells. BMC Neurosci 12: 82.    

28. Choi SH, Kim YH, Hebisch M, et al. (2014) A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 515: 274–278.    

29. Atherton J, Kurbatskaya K, Bondulich M, et al. (2014) Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Abeta in Alzheimer's disease. Aging Cell 13: 49–59.    

30. Ben-Ari Y, Khazipov R, Leinekugel X, et al. (1997) GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci 20: 523–529.    

31. Jiang Y, Zhang MJ, Hu BY (2012) Specification of functional neurons and glia from human pluripotent stem cells. Protein Cell 3: 818–825.    

32. Cummings DM, Brunjes PC (1994) Changes in cell proliferation in the developing olfactory epithelium following neonatal unilateral naris occlusion. Exp Neurol 128: 124–128.    

33. Hack MA, Saghatelyan A, de Chevigny A, et al. (2005) Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci 8: 865–872.    

34. Pires F, Ferreira Q, Rodrigues CA, et al. (2015) Neural stem cell differentiation by electrical stimulation using a cross-linked PEDOT substrate: Expanding the use of biocompatible conjugated conductive polymers for neural tissue engineering. Biochim Biophys Acta 1850: 1158–1168.    

35. Bardy C, van den Hurk M, Eames T, et al. (2015) Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci U S A 112: E2725–2734.    

36. Nissan X, Blondel S, Peschanski M (2011) In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria. Biochem Soc Trans 39: 1775–1779.    

37. Miller JD, Ganat YM, Kishinevsky S, et al. (2013) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13: 691–705.    

38. Moore DL, Pilz GA, Arauzo-Bravo MJ, et al. (2015) A mechanism for the segregation of age in mammalian neural stem cells. Science 349: 1334–1338.    

39. Ambasudhan R, Talantova M, Coleman R, et al. (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9: 113–118.    

40. Pang ZP, Yang N, Vierbuchen T, et al. (2011) Induction of human neuronal cells by defined transcription factors. Nature 476: 220–223.    

41. Caiazzo M, Dell'Anno MT, Dvoretskova E, et al. (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476: 224–227.    

42. Yoo AS, Sun AX, Li L, et al. (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476: 228–231.    

43. Mertens J, Paquola AC, Ku M, et al. (2015) Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell 17: 705–718.    

44. Kim J, Su SC, Wang H, et al. (2011) Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9: 413–419.    

45. Gunhanlar N, Shpak G, van der Kroeg M, et al. (2017) A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells. Mol Psychiatry.

46. Zhong P, Hu Z, Jiang H, et al. (2017) Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations. Cell Rep 19: 1033–1044.    

47. Wakeman DR, Hiller BM, Marmion DJ, et al. (2017) Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo. Stem Cell Reports 9: 149–161.    

48. Pre D, Nestor MW, Sproul AA, et al. (2014) A time course analysis of the electrophysiological properties of neurons differentiated from human induced pluripotent stem cells (iPSCs). PLoS One 9: e103418.    

49. Li GN, Livi LL, Gourd CM, et al. (2007) Genomic and morphological changes of neuroblastoma cells in response to three-dimensional matrices. Tissue Eng 13: 1035–1047.    

50. Navaei-Nigjeh M, Amoabedini G, Noroozi A, et al. (2014) Enhancing neuronal growth from human endometrial stem cells derived neuron-like cells in three-dimensional fibrin gel for nerve tissue engineering. J Biomed Mater Res A 102: 2533–2543.    

51. Yan W, Liu W, Qi J, et al. (2017) A Three-Dimensional Culture System with Matrigel Promotes Purified Spiral Ganglion Neuron Survival and Function In Vitro. Mol Neurobiol. doi: 10.1007/s12035-017-0471-0.

52. Chandrasekaran A, Avci HX, Ochalek A, et al. (2017) Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells. Stem Cell Res 25: 139–151.    

53. Jiang Z, Song Q, Tang M, et al. (2016) Enhanced Migration of Neural Stem Cells by Microglia Grown on a Three-Dimensional Graphene Scaffold. ACS Appl Mater Interfaces 8: 25069–25077.    

54. Lancaster MA, Renner M, Martin CA, et al. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501: 373–379.    

55. Garcez PP, Loiola EC, Madeiro da Costa R, et al. (2016) Zika virus impairs growth in human neurospheres and brain organoids. Science 352: 816–818.    

56. Qian X, Nguyen HN, Song MM, et al. (2016) Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell 165: 1238–1254.    

57. Cugola FR, Fernandes IR, Russo FB, et al. (2016) The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534: 267–271.    

58. Gabriel E, Ramani A, Karow U, et al. (2017) Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids. Cell Stem Cell 20: 397–406.    

59. Xu M, Lee EM, Wen Z, et al. (2016) Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 22: 1101–1107.    

60. Sacramento CQ, de Melo GR, de Freitas CS, et al. (2017) The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci Rep 7: 40920.    

61. Zhou T, Tan L, Cederquist GY, et al. (2017) High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. Cell Stem Cell 21: 274–283.    

62. Andersson M, Avaliani N, Svensson A, et al. (2016) Optogenetic control of human neurons in organotypic brain cultures. Sci Rep 6: 24818.    

63. Shimizu F, Hovinga KE, Metzner M, et al. (2011) Organotypic explant culture of glioblastoma multiforme and subsequent single-cell suspension. Curr Protoc Stem Cell Biol Chapter 3: Unit3.5.

64. Merz F, Gaunitz F, Dehghani F, et al. (2013) Organotypic slice cultures of human glioblastoma reveal different susceptibilities to treatments. Neuro Oncol 15: 670–681.    

65. Eugene E, Cluzeaud F, Cifuentes-Diaz C, et al. (2014) An organotypic brain slice preparation from adult patients with temporal lobe epilepsy. J Neurosci Methods 235: 234–244.    

66. Verwer RW, Sluiter AA, Balesar RA, et al. (2015) Injury Response of Resected Human Brain Tissue In Vitro. Brain Pathol 25: 454–468.    

67. Schwarz N, Hedrich UBS, Schwarz H, et al. (2017) Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Sci Rep 7: 12249.    

68. Sebollela A, Freitas-Correa L, Oliveira FF, et al. (2012) Amyloid-beta oligomers induce differential gene expression in adult human brain slices. J Biol Chem 287: 7436–7445.    

69. Bailey JL, O'Connor V, Hannah M, et al. (2011) In vitro CNS tissue analogues formed by self-organisation of reaggregated post-natal brain tissue. J Neurochem 117: 1020–1032.    

70. Schwartz MP, Hou Z, Propson NE, et al. (2015) Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A 112: 12516–12521.    

71. Crowder SW, Prasai D, Rath R, et al. (2013) Three-dimensional graphene foams promote osteogenic differentiation of human mesenchymal stem cells. Nanoscale 5: 4171–4176.    

72. Zong X, Bien H, Chung CY, et al. (2005) Electrospun fine-textured scaffolds for heart tissue constructs. Biomaterials 26: 5330–5338.    

73. Jakobsson A, Ottosson M, Zalis MC, et al. (2017) Three-dimensional functional human neuronal networks in uncompressed low-density electrospun fiber scaffolds. Nanomedicine 13: 1563–1573.    

74. Ma Q, Yang L, Jiang Z, et al. (2016) Three-Dimensional Stiff Graphene Scaffold on Neural Stem Cells Behavior. ACS Appl Mater Interfaces 8: 34227–34233.    

75. Li N, Zhang Q, Gao S, et al. (2013) Three-dimensional graphene foam as a biocompatible and conductive scaffold for neural stem cells. Sci Rep 3: 1604.    

76. Amato L, Heiskanen A, Caviglia C, et al. (2014) Pyrolysed 3D-Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real-Time Dopamine Detection. Adv Funct Mater 24: 7042–7052.    

77. Lutolf MP, Lauer-Fields JL, Schmoekel HG, et al. (2003) Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci U S A 100: 5413–5418.    

78. Stukel JM, Willits RK (2017) The interplay of peptide affinity and scaffold stiffness on neuronal differentiation of neural stem cells. Biomed Mater 13: 024102.

79. Sun G, Liu W, Fan Z, et al. (2016) The Three-Dimensional Culture System with Matrigel and Neurotrophic Factors Preserves the Structure and Function of Spiral Ganglion Neuron In Vitro. Neural Plast 2016: 4280407.

80. Kothapalli CR, Kamm RD (2013) 3D matrix microenvironment for targeted differentiation of embryonic stem cells into neural and glial lineages. Biomaterials 34: 5995–6007.    

81. Zhang D, Yang S, Toledo EM, et al. (2017) Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP. Sci Signal 10. pii: eaal4165

82. Dauth S, Grevesse T, Pantazopoulos H, et al. (2016) Extracellular matrix protein expression is brain region dependent. J Comp Neurol 524: 1309–1336.    

83. Arani A, Murphy MC, Glaser KJ, et al. (2015) Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults. Neuroimage 111: 59–64.    

84. Murphy MC, Huston J, Jack CR, et al. (2011) Decreased brain stiffness in Alzheimer's disease determined by magnetic resonance elastography. J Magn Reson Imaging 34: 494–498.    

85. Madl CM, LeSavage BL, Dewi RE, et al. (2017) Maintenance of neural progenitor cell stemness in 3D hydrogels requires matrix remodelling. Nat Mater 16: 1233–1242.    

86. Yildiz-Ozturk E, Gulce-Iz S, Anil M, et al. (2017) Cytotoxic responses of carnosic acid and doxorubicin on breast cancer cells in butterfly-shaped microchips in comparison to 2D and 3D culture. Cytotechnology 69: 337–347.    

87. Choi SH, Kim YH, Quinti L, et al. (2016) 3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish". Mol Neurodegener 11: 75.    

88. Yagi T, Ito D, Okada Y, et al. (2011) Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet 20: 4530–4539.    

89. Verheyen A, Diels A, Dijkmans J, et al. (2015) Using Human iPSC-Derived Neurons to Model TAU Aggregation. PLoS One 10: e0146127.    

90. Medda X, Mertens L, Versweyveld S, et al. (2016) Development of a Scalable, High-Throughput-Compatible Assay to Detect Tau Aggregates Using iPSC-Derived Cortical Neurons Maintained in a Three-Dimensional Culture Format. J Biomol Screen 21: 804–815.    

91. Wren MC, Zhao J, Liu CC, et al. (2015) Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener 10: 46.    

92. Ehrlich M, Hallmann AL, Reinhardt P, et al. (2015) Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein. Stem Cell Reports 5: 83–96.    

93. Mudher AK, Woolley ST, Perry VH, et al. (1999) Induction of hyperphosphorylated tau in living slices of rat hippocampal formation and subsequent detection using an ELISA. J Neurosci Methods 88: 15–25.    

94. Seubert P, Mawal-Dewan M, Barbour R, et al. (1995) Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau. J Biol Chem 270: 18917–18922.    

95. Matsuo ES, Shin RW, Billingsley ML, et al. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron 13: 989–1002.    

96. Muratore CR, Rice HC, Srikanth P, et al. (2014) The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23: 3523–3536.    

97. Israel MA, Yuan SH, Bardy C, et al. (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482: 216–220.    

98. Zempel H, Thies E, Mandelkow E, et al. (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30: 11938–11950.    

99. Raja WK, Mungenast AE, Lin YT, et al. (2016) Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One 11: e0161969.    

100. Kurbatskaya K, Phillips EC, Croft CL, et al. (2016) Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer's disease brain. Acta Neuropathol Commun 4: 34.    

101. Jones VC, Atkinson-Dell R, Verkhratsky A, et al. (2017) Aberrant iPSC-derived human astrocytes in Alzheimer's disease. Cell Death Dis 8: e2696.    

102. Lee HK, Velazquez Sanchez C, Chen M, et al. (2016) Three Dimensional Human Neuro-Spheroid Model of Alzheimer's Disease Based on Differentiated Induced Pluripotent Stem Cells. PLoS One 11: e0163072.    

103. Zhang D, Pekkanen-Mattila M, Shahsavani M, et al. (2014) A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons. Biomaterials 35: 1420–1428.    

104. Pamies D, Barreras P, Block K, et al. (2017) A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity. ALTEX 34: 362–376.

105. Skaper SD, Facci L, Zusso M, et al. (2017) Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol Disord Drug Targets 16: 220–233.    

106. Chakroborty S, Stutzmann GE (2011) Early calcium dysregulation in Alzheimer's disease: setting the stage for synaptic dysfunction. Sci China Life Sci 54: 752–762.    

107. Terwel D, Dewachter I, Van Leuven F (2002) Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease. Neuromolecular Med 2: 151–165.    

108. Mudher A, Shepherd D, Newman TA, et al. (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9: 522–530.    

109. Morris M, Knudsen GM, Maeda S, et al. (2015) Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci 18: 1183–1189.    

110. Hogberg HT, Bressler J, Christian KM, et al. (2013) Toward a 3D model of human brain development for studying gene/environment interactions. Stem Cell Res Ther 4 Suppl 1: S4.

111. Roybon L, Lamas NJ, Garcia AD, et al. (2013) Human stem cell-derived spinal cord astrocytes with defined mature or reactive phenotypes. Cell Rep 4: 1035–1048.    

112. Shaltouki A, Peng J, Liu Q, et al. (2013) Efficient generation of astrocytes from human pluripotent stem cells in defined conditions. Stem Cells 31: 941–952.    

113. Wang S, Bates J, Li X, et al. (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12: 252–264.    

114. Douvaras P, Wang J, Zimmer M, et al. (2014) Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports 3: 250–259.    

115. Nieweg K, Andreyeva A, van Stegen B, et al. (2015) Alzheimer's disease-related amyloid-beta induces synaptotoxicity in human iPS cell-derived neurons. Cell Death Dis 6: e1709.    

116. Hu BY, Zhang SC (2009) Differentiation of spinal motor neurons from pluripotent human stem cells. Nat Protoc 4: 1295–1304.    

117. Yan Y, Bejoy J, Xia J, et al. (2016) Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses. Acta Biomater 42: 114–126.    

118. Jiang H, Ren Y, Yuen EY, et al. (2012) Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun 3: 668.    

119. Cooper O, Hargus G, Deleidi M, et al. (2010) Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol Cell Neurosci 45: 258–266.    

120. Vazin T, Ball KA, Lu H, et al. (2014) Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease. Neurobiol Dis 62: 62–72.    

121. Wang C, Ward ME, Chen R, et al. (2017) Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports 9: 1221–1233.    

122. Vazin T, Ashton RS, Conway A, et al. (2014) The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons. Biomaterials 35: 941–948.    

123. Lu J, Zhong X, Liu H, et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34: 89–94.    

124. Smith I, Silveirinha V, Stein JL, et al. (2017) Human neural stem cell-derived cultures in three-dimensional substrates form spontaneously functional neuronal networks. J Tissue Eng Regen Med 11: 1022–1033.    

125. Ballios BG, Cooke MJ, Donaldson L, et al. (2015) A Hyaluronan-Based Injectable Hydrogel Improves the Survival and Integration of Stem Cell Progeny following Transplantation. Stem Cell Reports 4: 1031–1045.    

126. Shepard JA, Stevans AC, Holland S, et al. (2012) Hydrogel design for supporting neurite outgrowth and promoting gene delivery to maximize neurite extension. Biotechnol Bioeng 109: 830–839.    

127. Saha K, Keung AJ, Irwin EF, et al. (2008) Substrate modulus directs neural stem cell behavior. Biophys J 95: 4426–4438.    

128. Banerjee A, Arha M, Choudhary S, et al. (2009) The influence of hydrogel modulus on the proliferation and differentiation of encapsulated neural stem cells. Biomaterials 30: 4695–4699.    

129. Previtera ML, Hui M, Verma D, et al. (2013) The effects of substrate elastic modulus on neural precursor cell behavior. Ann Biomed Eng 41: 1193–1207.    

130. Shah S, Yin PT, Uehara TM, et al. (2014) Guiding stem cell differentiation into oligodendrocytes using graphene-nanofiber hybrid scaffolds. Adv Mater 26: 3673–3680.    

131. Vargas-Caballero M, Willaime-Morawek S, Gomez-Nicola D, et al. (2016) The use of human neurons for novel drug discovery in dementia research. Expert Opin Drug Discov 11: 355–367.    

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