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Modeling Psychiatric Disorder Biology with Stem Cells

  • Genetic Disorders (F Goes, Section Editor)
  • Published:
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Abstract

Purpose of Review

We review the ways in which stem cells are used in psychiatric disease research, including the related advances in gene editing and directed cell differentiation.

Recent Findings

The recent development of induced pluripotent stem cell (iPSC) technologies has created new possibilities for the study of psychiatric disease. iPSCs can be derived from patients or controls and differentiated to an array of neuronal and non-neuronal cell types. Their genomes can be edited as desired, and they can be assessed for a variety of phenotypes. This makes them especially interesting for studying genetic variation, which is particularly useful today now that our knowledge on the genetics of psychiatric disease is quickly expanding.

Summary

The recent advances in cell engineering have led to powerful new methods for studying psychiatric illness including schizophrenia, bipolar disorder, and autism. There is a wide array of possible applications as illustrated by the many examples from the literature, most of which are cited here.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Consortium SWGotPG. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.

    Article  CAS  Google Scholar 

  3. Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50(3):381–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Avramopoulos D. Recent advances in the genetics of schizophrenia. Mol Neuropsychiatry. 2018;4(1):35–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51(3):431–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Arnett AB, Trinh S, Bernier RA. The state of research on the genetics of autism spectrum disorder: methodological, clinical and conceptual progress. Curr Opin Psychol. 2019;27:1–5.

    Article  PubMed  Google Scholar 

  7. Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51(5):793–803.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Goes FS. Genetics of bipolar disorder: recent update and future directions. Psychiatr Clin North Am. 2016;39(1):139–55.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50(5):668–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Doherty JL, Owen MJ. Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice. Genome Med. 2014;6(4):29.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45(9):984–94.

    Article  PubMed  CAS  Google Scholar 

  12. Kvajo M, McKellar H, Gogos JA. Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. Neuroscience. 2012;211:136–64.

    Article  PubMed  CAS  Google Scholar 

  13. Kannan G, Sawa A, Pletnikov MV. Mouse models of gene-environment interactions in schizophrenia. Neurobiol Dis. 2013;57:5–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Pletnikov MV. Inducible and conditional transgenic mouse models of schizophrenia. Prog Brain Res. 2009;179:35–47.

    Article  PubMed  CAS  Google Scholar 

  15. Kazdoba TM, Leach PT, Crawley JN. Behavioral phenotypes of genetic mouse models of autism. Genes Brain Behav. 2016;15(1):7–26.

    Article  PubMed  CAS  Google Scholar 

  16. Hui K, Katayama Y, Nakayama KI, Nomura J, Sakurai T. Characterizing vulnerable brain areas and circuits in mouse models of autism: towards understanding pathogenesis and new therapeutic approaches. Neurosci Biobehav Rev. 2018;110:77–91.

    Article  PubMed  Google Scholar 

  17. •• Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Nature. 1997;385(6619):810–3. The first cloning experiment showing that a somatic nucleus can be reprogrammed.

  18. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  PubMed  CAS  Google Scholar 

  19. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007;448(7151):318–24.

    Article  PubMed  CAS  Google Scholar 

  20. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1(1):55–70.

    Article  PubMed  CAS  Google Scholar 

  21. •• Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20. This paper first describes making iPSCs from human somatic cells.

    Article  PubMed  CAS  Google Scholar 

  22. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008;451(7175):141–6.

    Article  PubMed  CAS  Google Scholar 

  23. Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A. 2008;105(8):2883–8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell. 2009;5(1):111–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467(7313):285–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Azevedo JL, Feldman RA. Tinkering with transcription factors uncovers plasticity of somatic cells. Genes Cancer. 2010;1(11):1089–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Cahan P, Daley GQ. Origins and implications of pluripotent stem cell variability and heterogeneity. Nat Rev Mol Cell Biol. 2013;14(6):357–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yasuhara T, Kawauchi S, Kin K, Morimoto J, Kameda M, Sasaki T, et al. Cell therapy for central nervous system disorders: current obstacles to progress. CNS Neurosci Ther. 2019.

  29. Tao Y, Zhang SC. Neural subtype specification from human pluripotent stem cells. Cell Stem Cell. 2016;19(5):573–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 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(6):703–14.

    Article  PubMed  CAS  Google Scholar 

  31. Kiecker C, Lumsden A. The role of organizers in patterning the nervous system. Annu Rev Neurosci. 2012;35:347–67.

    Article  PubMed  CAS  Google Scholar 

  32. Le Dreau G, Marti E. Dorsal-ventral patterning of the neural tube: a tale of three signals. Dev Neurobiol. 2012;72(12):1471–81.

    Article  PubMed  CAS  Google Scholar 

  33. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27(3):275–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Mertens J, Marchetto MC, Bardy C, Gage FH. Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci. 2016;17(7):424–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, et al. Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev. 2009;23(5):561–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Ozair MZ, Kintner C, Brivanlou AH. Neural induction and early patterning in vertebrates. Wiley Interdiscip Rev Dev Biol. 2013;2(4):479–98.

    Article  PubMed  CAS  Google Scholar 

  37. Stern CD. Neural induction: old problem, new findings, yet more questions. Development. 2005;132(9):2007–21.

    Article  PubMed  CAS  Google Scholar 

  38. Stern CD. Neural induction: 10 years on since the ‘default model’. Curr Opin Cell Biol. 2006;18(6):692–7.

    Article  PubMed  CAS  Google Scholar 

  39. Stern CD, Charite J, Deschamps J, Duboule D, Durston AJ, Kmita M, et al. Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems? Int J Dev Biol. 2006;50(1):3–15.

    Article  PubMed  CAS  Google Scholar 

  40. Wilson SW, Houart C. Early steps in the development of the forebrain. Dev Cell. 2004;6(2):167–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Nikolopoulou E, Galea GL, Rolo A, Greene ND, Copp AJ. Neural tube closure: cellular, molecular and biomechanical mechanisms. Development. 2017;144(4):552–66.

    Article  PubMed  CAS  Google Scholar 

  42. Greene ND, Copp AJ. Neural tube defects. Annu Rev Neurosci. 2014;37:221–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Beccari L, Marco-Ferreres R, Bovolenta P. The logic of gene regulatory networks in early vertebrate forebrain patterning. Mech Dev. 2013;130(2–3):95–111.

    Article  PubMed  CAS  Google Scholar 

  44. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7(2):136–44.

    Article  PubMed  CAS  Google Scholar 

  45. Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008;455(7211):351–7.

    Article  PubMed  CAS  Google Scholar 

  46. Sur M, Rubenstein JL. Patterning and plasticity of the cerebral cortex. Science. 2005;310(5749):805–10.

    Article  PubMed  CAS  Google Scholar 

  47. Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute T, Zhang SC. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 2009;136(23):4055–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S, Kawasaki H, et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci. 2005;8(3):288–96.

    Article  PubMed  CAS  Google Scholar 

  49. 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(5):519–32.

    Article  PubMed  CAS  Google Scholar 

  50. Shi Y, Kirwan P, Livesey FJ. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc. 2012;7(10):1836–46.

    Article  PubMed  CAS  Google Scholar 

  51. Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci. 2012;15(3):477–86 s471.

    Article  PubMed  CAS  Google Scholar 

  52. Leone DP, Srinivasan K, Chen B, Alcamo E, McConnell SK. The determination of projection neuron identity in the developing cerebral cortex. Curr Opin Neurobiol. 2008;18(1):28–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Espuny-Camacho I, Michelsen KA, Gall D, Linaro D, Hasche A, Bonnefont J, et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron. 2013;77(3):440–56.

    Article  PubMed  CAS  Google Scholar 

  54. • Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373–9. Generation of human brain organoids.

    Article  PubMed  CAS  Google Scholar 

  55. • 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(7346):221–5. The earliest study where schizophrenia patient iPSCs were generated and compared to controls.

  56. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria K, et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry. 2017;22(6):820–35.

    Article  PubMed  CAS  Google Scholar 

  57. Mariani J, Simonini MV, Palejev D, Tomasini L, Coppola G, Szekely AM, et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012;109(31):12770–5.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N, Vogt D, et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell. 2013;12(5):573–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. •• Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463(7284):1035–41. The first direct induction to neurons.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, et al. Induction of human neuronal cells by defined transcription factors. Nature. 2011;476(7359):220–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, et al. MicroRNA-mediated conversion of human fibroblasts to neuronsm. Nature. 2011;476(7359):228–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z, Chanda S, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013;78(5):785–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, et al. Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Reports. 2014;3(2):282–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Busskamp V, Lewis NE, Guye P, Ng AH, Shipman SL, Byrne SM, et al. Rapid neurogenesis through transcriptional activation in human stem cells. Mol Syst Biol. 2014;10:760.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Liu ML, Zang T, Zou Y, Chang JC, Gibson JR, Huber KM, et al. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun. 2013;4:2183.

    Article  PubMed  CAS  Google Scholar 

  66. Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000;127(3):457–67.

    PubMed  CAS  Google Scholar 

  67. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10(9):1110–5.

    Article  PubMed  CAS  Google Scholar 

  68. Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S, et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry. 2013;3:e210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006;11(5):514–22.

    Article  PubMed  CAS  Google Scholar 

  70. Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia. Am J Psychiatry. 2010;167(10):1178–93.

    Article  PubMed  Google Scholar 

  71. Walton NM, Zhou Y, Kogan JH, Shin R, Webster M, Gross AK, et al. Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients. Transl Psychiatry. 2012;2:e135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Hagihara H, Takao K, Walton NM, Matsumoto M, Miyakawa T. Immature dentate gyrus: an endophenotype of neuropsychiatric disorders. Neural Plast. 2013;2013:318596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports. 2014;2(3):295–310.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Mertens J, Wang QW, 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(7576):95–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Galceran J, Miyashita-Lin EM, Devaney E, Rubenstein JL, Grosschedl R. Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1. Development. 2000;127(3):469–82.

    PubMed  CAS  Google Scholar 

  76. Sarkar A, Mei A, Paquola ACM, Stern S, Bardy C, Klug JR, et al. Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro. Cell Stem Cell. 2018;22(5):684–697.e689.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wonders CP, Anderson SA. The origin and specification of cortical interneurons. Nat Rev Neurosci. 2006;7(9):687–96.

    Article  PubMed  CAS  Google Scholar 

  78. Kelsom C, Lu W. Development and specification of GABAergic cortical interneurons. Cell Biosci. 2013;3(1):19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci. 2010;30(50):16796–808.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Kepecs A, Fishell G. Interneuron cell types are fit to function. Nature. 2014;505(7483):318–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Miyoshi G, Hjerling-Leffler J, Karayannis T, Sousa VH, Butt SJ, Battiste J, et al. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J Neurosci. 2010;30(5):1582–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Ihnatovych I, Lew A, Lazar E, Sheng A, Kellermayer T, Szigeti K. Timing of Wnt inhibition modulates directed differentiation of medial ganglionic eminence progenitors from human pluripotent stem cells. Stem Cells Int. 2018;2018:3983090.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ahn S, Kim TG, Kim KS, Chung S. Differentiation of human pluripotent stem cells into medial ganglionic eminence vs. caudal ganglionic eminence cells. Methods. 2016;101:103–12.

    Article  PubMed  CAS  Google Scholar 

  84. Anderson NC, Chen CY, Grabel L. Hedgehog promotes production of inhibitory interneurons in vivo and in vitro from pluripotent stem cells. J Dev Biol. 2016;4(3):E26.

    Article  PubMed  CAS  Google Scholar 

  85. Liu Y, Liu H, Sauvey C, Yao L, Zarnowska ED, Zhang SC. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc. 2013;8(9):1670–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM, Merkle FT, et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013;12(5):559–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Mayer C, Hafemeister C, Bandler RC, Machold R, Batista Brito R, Jaglin X, et al. Developmental diversification of cortical inhibitory interneurons. Nature. 2018;555(7697):457–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Shao Z, Noh H, Bin Kim W, Ni P, Nguyen C, Cote SE, et al. Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci. 2019;22(2):229–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ni P, Noh H, Park GH, Shao Z, Guan Y, Park JM, Yu S, Park JS, Coyle JT, Weinberger DR et al: iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function. Mol Psychiatry 2019.

  90. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science. 1998;280(5369):1610–3.

    Article  PubMed  CAS  Google Scholar 

  91. Kassmann CM, Lappe-Siefke C, Baes M, Brugger B, Mildner A, Werner HB, et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet. 2007;39(8):969–76.

    Article  PubMed  CAS  Google Scholar 

  92. Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet. 2003;33(3):366–74.

    Article  PubMed  CAS  Google Scholar 

  93. Rodrigues GMC, Gaj T, Adil MM, Wahba J, Rao AT, Lorbeer FK, et al. Defined and scalable differentiation of human oligodendrocyte precursors from pluripotent stem cells in a 3D culture system. Stem Cell Reports. 2017;8(6):1770–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Emery B. Transcriptional and post-transcriptional control of CNS myelination. Curr Opin Neurobiol. 2010;20(5):601–7.

    Article  PubMed  CAS  Google Scholar 

  95. Richardson WD, Kessaris N, Pringle N. Oligodendrocyte wars. Nat Rev Neurosci. 2006;7(1):11–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Hu BY, Du ZW, Zhang SC. Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc. 2009;4(11):1614–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25(19):4694–705.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005;49(3):385–96.

    Article  PubMed  Google Scholar 

  99. Kerr CL, Letzen BS, Hill CM, Agrawal G, Thakor NV, Sterneckert JL, et al. Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury. Int J Neurosci. 2010;120(4):305–13.

    Article  PubMed  CAS  Google Scholar 

  100. Sharp J, Frame J, Siegenthaler M, Nistor G, Keirstead HS. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells. 2010;28(1):152–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  101. Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell. 2013;12(2):252–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Piao J, Major T, Auyeung G, Policarpio E, Menon J, Droms L, et al. Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell. 2015;16(2):198–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Yang N, Zuchero JB, Ahlenius H, Marro S, Ng YH, Vierbuchen T, et al. Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol. 2013;31(5):434–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Madhavan M, Nevin ZS, Shick HE, Garrison E, Clarkson-Paredes C, Karl M, et al. Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods. 2018;15(9):700–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A. 2001;98(8):4746–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Sugai T, Kawamura M, Iritani S, Araki K, Makifuchi T, Imai C, et al. Prefrontal abnormality of schizophrenia revealed by DNA microarray: impact on glial and neurotrophic gene expression. Ann N Y Acad Sci. 2004;1025:84–91.

    Article  PubMed  CAS  Google Scholar 

  107. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet. 2003;362(9386):798–805.

    Article  PubMed  CAS  Google Scholar 

  108. Nave KA, Ehrenreich H. Myelination and oligodendrocyte functions in psychiatric diseases. JAMA Psychiatry. 2014;71(5):582–4.

    Article  PubMed  Google Scholar 

  109. Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18(7):942–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Zhang Y, Barres BA. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol. 2010;20(5):588–94.

    Article  PubMed  CAS  Google Scholar 

  111. Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods Mol Biol. 2012;814:23–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Freeman MR. Specification and morphogenesis of astrocytes. Science. 2010;330(6005):774–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 2012;26(9):891–907.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Reemst K, Noctor SC, Lucassen PJ, Hol EM. The indispensable roles of microglia and astrocytes during brain development. Front Hum Neurosci. 2016;10:566.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000;101(5):499–510.

    Article  PubMed  CAS  Google Scholar 

  116. Krencik R, Zhang SC. Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc. 2011;6(11):1710–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Krencik R, Weick JP, Liu Y, Zhang ZJ, Zhang SC. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol. 2011;29(6):528–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Santos R, Vadodaria KC, Jaeger BN, Mei A, Lefcochilos-Fogelquist S, Mendes APD, et al. Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Reports. 2017;8(6):1757–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  120. Wolf SA, Boddeke HW, Kettenmann H. Microglia in physiology and disease. Annu Rev Physiol. 2017;79:619–43.

    Article  CAS  PubMed  Google Scholar 

  121. Sierra A, Beccari S, Diaz-Aparicio I, Encinas JM, Comeau S, Tremblay ME. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis. Neural Plast. 2014;2014:610343.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Neniskyte U, Gross CT. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18(11):658–70.

    Article  PubMed  CAS  Google Scholar 

  123. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982;17(4):319–34.

    Article  PubMed  Google Scholar 

  124. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci. 2013;16(3):273–80.

    Article  PubMed  CAS  Google Scholar 

  126. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336(6077):86–90.

    Article  PubMed  CAS  Google Scholar 

  127. Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity. 2012;37(6):1050–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol. 2012;13(8):753–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014;211(8):1533–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17(1):131–43.

    Article  PubMed  CAS  Google Scholar 

  131. Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016;22(11):1358–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Pandya H, Shen MJ, Ichikawa DM, Sedlock AB, Choi Y, Johnson KR, et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 2017;20(5):753–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 2017;94(2):278–293.e279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, Blurton-Jones M. Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Mol Neurodegener. 2018;13(1):67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Petanjek Z, Judas M, Simic G, Rasin MR, Uylings HB, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci U S A. 2011;108(32):13281–6.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Cannon TD. How schizophrenia develops: cognitive and brain mechanisms underlying onset of psychosis. Trends Cogn Sci. 2015;19(12):744–56.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22(3):374–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515(7527):414–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Johnstone M, Fetit R. HippoCA3mpal stem cell models expose dysfunctional circuits in schizophrenia. Cell Stem Cell. 2018;22(5):609–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Cirillo MA, Seidman LJ. Verbal declarative memory dysfunction in schizophrenia: from clinical assessment to genetics and brain mechanisms. Neuropsychol Rev. 2003;13(2):43–77.

    Article  PubMed  Google Scholar 

  142. Freedman R, Goldowitz D. Studies on the hippocampal formation: From basic development to clinical applications: studies on schizophrenia. Prog Neurobiol. 2010;90(2):263–75.

    Article  PubMed  CAS  Google Scholar 

  143. Rasetti R, Mattay VS, White MG, Sambataro F, Podell JE, Zoltick B, et al. Altered hippocampal-parahippocampal function during stimulus encoding: a potential indicator of genetic liability for schizophrenia. JAMA Psychiatry. 2014;71(3):236–47.

    Article  PubMed  Google Scholar 

  144. Kolomeets NS, Orlovskaya DD, Uranova NA. Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia. Synapse. 2007;61(8):615–21.

    Article  PubMed  CAS  Google Scholar 

  145. Li W, Ghose S, Gleason K, Begovic A, Perez J, Bartko J, et al. Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia. Am J Psychiatry. 2015;172(4):373–82.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472(7341):51–6.

    Article  PubMed  CAS  Google Scholar 

  147. Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):771–85.

    Article  PubMed  CAS  Google Scholar 

  148. Garcez PP, Loiola EC. Madeiro da Costa R, Higa LM, Trindade P, Delvecchio R, Nascimento JM, Brindeiro R, Tanuri A, Rehen SK: Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016;352(6287):816–8.

    Article  PubMed  CAS  Google Scholar 

  149. Adams JW, Cugola FR, Muotri AR. Brain organoids as tools for modeling human neurodevelopmental disorders. Physiology (Bethesda). 2019;34(5):365–75.

    CAS  Google Scholar 

  150. Stachowiak EK, Benson CA, Narla ST, Dimitri A, Chuye LEB, Dhiman S, et al. Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1. Transl Psychiatry. 2017;7(11):6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. van den Hurk M, Bardy C. Single-cell multimodal transcriptomics to study neuronal diversity in human stem cell-derived brain tissue and organoid models. J Neurosci Methods. 2019;325:108350.

    Article  PubMed  CAS  Google Scholar 

  152. Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, Smillie C, et al. A single-cell survey of the small intestinal epithelium. Nature. 2017;551(7680):333–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570(7762):523–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Deriano L, Roth DB. Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet. 2013;47:433–55.

    Article  PubMed  CAS  Google Scholar 

  155. Chakrabarti AM, Henser-Brownhill T, Monserrat J, Poetsch AR, Luscombe NM, Scaffidi P. Target-specific precision of CRISPR-mediated genome editing. Mol Cell. 2019;73(4):699–713.e696.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Tan EP, Li Y, Velasco-Herrera Mdel C, Yusa K, Bradley A. Off-target assessment of CRISPR-Cas9 guiding RNAs in human iPS and mouse ES cells. Genesis. 2015;53(2):225–36.

    Article  PubMed  CAS  Google Scholar 

  157. Chen F, Pruett-Miller SM, Huang Y, Gjoka M, Duda K, Taunton J, et al. High-frequency genome editing using ssDNA oligonucleotides with zinc-finger nucleases. Nat Methods. 2011;8(9):753–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Yang L, Guell M, Byrne S, Yang JL, De Los AA, Mali P, et al. Optimization of scarless human stem cell genome editing. Nucleic Acids Res. 2013;41(19):9049–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Yu C, Liu Y, Ma T, Liu K, Xu S, Zhang Y, et al. Small molecules enhance CRISPR genome editing in pluripotent stem cells. Cell Stem Cell. 2015;16(2):142–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Yumlu S, Bashir S, Stumm J, Kuhn R. Efficient gene editing of human induced pluripotent stem cells using CRISPR/Cas9. Methods Mol Biol. 1961;2019:137–51.

    Google Scholar 

  161. Byrne SM, Church GM. Crispr-mediated gene targeting of human induced pluripotent stem cells. Curr Protoc Stem Cell Biol. 2015;35:5a.8.1–5a.8.22.

    Article  Google Scholar 

  162. Miyaoka Y, Chan AH, Judge LM, Yoo J, Huang M, Nguyen TD, et al. Isolation of single-base genome-edited human iPS cells without antibiotic selection. Nat Methods. 2014;11(3):291–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Yumlu S, Stumm J, Bashir S, Dreyer AK, Lisowski P, Danner E, et al. Gene editing and clonal isolation of human induced pluripotent stem cells using CRISPR/Cas9. Methods. 2017;121–122:29–44.

    Article  PubMed  CAS  Google Scholar 

  164. Sluch VM, Chamling X, Wenger C, Duan Y, Rice DS, Zack DJ. Highly efficient scarless knock-in of reporter genes into human and mouse pluripotent stem cells via transient antibiotic selection. PLoS One. 2018;13(11):e0201683.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Gupta N, Susa K, Yoda Y, Bonventre JV, Valerius MT, Morizane R. CRISPR/Cas9-based targeted genome editing for the development of monogenic diseases models with human pluripotent stem cells. Curr Protoc Stem Cell Biol. 2018;45(1):e50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A. 1996;93(3):1156–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF, et al. A TALE nuclease architecture for efficient genome editing. Nat Biotechnol. 2011;29(2):143–8.

    Article  PubMed  CAS  Google Scholar 

  168. Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver RC, et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol. 2009;27(9):851–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Soldner F, Laganiere J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell. 2011;146(2):318–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Zou J, Mali P, Huang X, Dowey SN, Cheng L. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood. 2011;118(17):4599–608.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Connelly JP, Kwon EM, Gao Y, Trivedi NS, Elkahloun AG, Horwitz MS, et al. Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects. Blood. 2014;124(12):1926–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol. 2011;29(8):731–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A, Kim K, et al. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell. 2013;12(2):238–51.

    Article  PubMed  CAS  Google Scholar 

  174. Gonzalez F, Zhu Z, Shi ZD, Lelli K, Verma N, Li QV, et al. An iCRISPR platform for rapid, multiplexable, and inducible genome editing in human pluripotent stem cells. Cell Stem Cell. 2014;15(2):215–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Ma N, Liao B, Zhang H, Wang L, Shan Y, Xue Y, et al. Transcription activator-like effector nuclease (TALEN)-mediated gene correction in integration-free beta-thalassemia induced pluripotent stem cells. J Biol Chem. 2013;288(48):34671–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Wu J, Kandavelou K, Chandrasegaran S. Custom-designed zinc finger nucleases: what is next? Cell Mol Life Sci. 2007;64(22):2933–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Joung JK, Sander JD. TALENs: a widely applicable technology for targeted genome editing. Nat Rev Mol Cell Biol. 2013;14(1):49–55.

    Article  PubMed  CAS  Google Scholar 

  178. •• Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21. The first description of the potential for genome editing by CRISPR/Cas9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Ding Q, Regan SN, Xia Y, Oostrom LA, Cowan CA, Musunuru K. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell. 2013;12(4):393–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Ye L, Wang J, Beyer AI, Teque F, Cradick TJ, Qi Z, et al. Seamless modification of wild-type induced pluripotent stem cells to the natural CCR5Delta32 mutation confers resistance to HIV infection. Proc Natl Acad Sci U S A. 2014;111(26):9591–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Saha SK, Saikot FK, Rahman MS, Jamal M, Rahman SMK, Islam SMR, et al. Programmable molecular scissors: applications of a new tool for genome editing in biotech. Mol Ther Nucleic Acids. 2019;14:212–38.

    Article  PubMed  CAS  Google Scholar 

  183. Musunuru K. Genome editing of human pluripotent stem cells to generate human cellular disease models. Dis Model Mech. 2013;6(4):896–904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Zhang Z, Zhang Y, Gao F, Han S, Cheah KS, Tse HF, et al. CRISPR/Cas9 genome-editing system in human stem cells: current status and future prospects. Mol Ther Nucleic Acids. 2017;9:230–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Ohgushi M, Matsumura M, Eiraku M, Murakami K, Aramaki T, Nishiyama A, et al. Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. Cell Stem Cell. 2010;7(2):225–39.

    Article  PubMed  CAS  Google Scholar 

  186. Chen G, Hou Z, Gulbranson DR, Thomson JA. Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells. Cell Stem Cell. 2010;7(2):240–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Byrne SM, Ortiz L, Mali P, Aach J, Church GM. Multi-kilobase homozygous targeted gene replacement in human induced pluripotent stem cells. Nucleic Acids Res. 2015;43(3):e21.

    Article  PubMed  CAS  Google Scholar 

  188. Byrne SM, Mali P, Church GM. Genome editing in human stem cells. Methods Enzymol. 2014;546:119–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. An MC, O'Brien RN, Zhang N, Patra BN, De La Cruz M, Ray A, Ellerby LM: Polyglutamine disease modeling: epitope based screen for homologous recombination using CRISPR/Cas9 system. PLoS Curr 2014, 6.

  190. Song B, Fan Y, He W, Zhu D, Niu X, Wang D, et al. Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system. Stem Cells Dev. 2015;24(9):1053–65.

    Article  PubMed  CAS  Google Scholar 

  191. Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24(7):927–30.

    Article  PubMed  CAS  Google Scholar 

  192. Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018;24(7):939–46.

    Article  PubMed  CAS  Google Scholar 

  193. Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T, et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol. 2007;25(6):681–6.

    Article  PubMed  CAS  Google Scholar 

  194. Li XL, Li GH, Fu J, Fu YW, Zhang L, Chen W, et al. Highly efficient genome editing via CRISPR-Cas9 in human pluripotent stem cells is achieved by transient BCL-XL overexpression. Nucleic Acids Res. 2018;46(19):10195–215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Kim S, Kim D, Cho SW, Kim J, Kim JS. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res. 2014;24(6):1012–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Zuris JA, Thompson DB, Shu Y, Guilinger JP, Bessen JL, Hu JH, et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol. 2015;33(1):73–80.

    Article  PubMed  CAS  Google Scholar 

  197. Vakulskas CA, Dever DP, Rettig GR, Turk R, Jacobi AM, Collingwood MA, et al. A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat Med. 2018;24(8):1216–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Skarnes WC, Pellegrino E, McDonough JA. Improving homology-directed repair efficiency in human stem cells. Methods. 2019;164–165:18–28.

    Article  PubMed  CAS  Google Scholar 

  199. Lin S, Staahl BT, Alla RK, Doudna JA. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. Elife. 2014;3:e04766.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Yang D, Scavuzzo MA, Chmielowiec J, Sharp R, Bajic A, Borowiak M. Enrichment of G2/M cell cycle phase in human pluripotent stem cells enhances HDR-mediated gene repair with customizable endonucleases. Sci Rep. 2016;6:21264.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Guo Q, Mintier G, Ma-Edmonds M, Storton D, Wang X, Xiao X, et al. Feder JN: ‘Cold shock’ increases the frequency of homology directed repair gene editing in induced pluripotent stem cells. Sci Rep. 2018;8(1):2080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Song J, Yang D, Xu J, Zhu T, Chen YE, Zhang J. RS-1 enhances CRISPR/Cas9- and TALEN-mediated knock-in efficiency. Nat Commun. 2016;7:10548.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Riesenberg S, Maricic T. Targeting repair pathways with small molecules increases precise genome editing in pluripotent stem cells. Nat Commun. 2018;9(1):2164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE. Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol. 2016;34(3):339–44.

    Article  PubMed  CAS  Google Scholar 

  205. Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S, et al. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature. 2016;533(7601):125–9.

    Article  PubMed  CAS  Google Scholar 

  206. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281–308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Shen B, Zhang W, Zhang J, Zhou J, Wang J, Chen L, et al. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects. Nat Methods. 2014;11(4):399–402.

    Article  PubMed  CAS  Google Scholar 

  208. Rees HA, Yeh WH, Liu DR. Development of hRad51-Cas9 nickase fusions that mediate HDR without double-stranded breaks. Nat Commun. 2019;10(1):2212.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Chen X, Janssen JM, Liu J. Maggio I, t Jong AEJ, Mikkers HMM, Goncalves M: In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting. Nat Commun. 2017;8(1):657.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Tu J, Huo Z, Liu M, Wang D, Xu A, Zhou R, et al. Generation of human embryonic stem cell line with heterozygous RB1 deletion by CRIPSR/Cas9 nickase. Stem Cell Res. 2018;28:29–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Jacobs EZ, Warrier S, Volders PJ, D'Haene E, Van Lombergen E, Vantomme L, et al. CRISPR/Cas9-mediated genome editing in naive human embryonic stem cells. Sci Rep. 2017;7(1):16650.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Hazelbaker DZ, Beccard A, Bara AM, Dabkowski N, Messana A, Mazzucato P, et al. A scaled framework for CRISPR editing of human pluripotent stem cells to study psychiatric disease. Stem Cell Reports. 2017;9(4):1315–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Eggenschwiler R, Moslem M, Fraguas MS, Galla M, Papp O, Naujock M, et al. Improved bi-allelic modification of a transcriptionally silent locus in patient-derived iPSC by Cas9 nickase. Sci Rep. 2016;6:38198.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Wu J, Hunt SD, Xue H, Liu Y, Darabi R. Generation and validation of PAX7 reporter lines from human iPS cells using CRISPR/Cas9 technology. Stem Cell Res. 2016;16(2):220–8.

    Article  PubMed  CAS  Google Scholar 

  215. Schrode N, Ho SM, Yamamuro K, Dobbyn A, Huckins L, Matos MR, et al. Synergistic effects of common schizophrenia risk variants. Nat Genet. 2019;51(10):1475–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Li C, Ding L, Sun CW, Wu LC, Zhou D, Pawlik KM, et al. Novel HDAd/EBV reprogramming vector and highly efficient Ad/CRISPR-Cas sickle cell disease gene correction. Sci Rep. 2016;6:30422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Moyer TC, Holland AJ. Generation of a conditional analog-sensitive kinase in human cells using CRISPR/Cas9-mediated genome engineering. Methods Cell Biol. 2015;129:19–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Alateeq S, Ovchinnikov D, Tracey T, Whitworth D, Al-Rubaish A, Al-Ali A, et al. Identification of on-target mutagenesis during correction of a beta-thalassemia splice mutation in iPS cells with optimised CRISPR/Cas9-double nickase reveals potential safety concerns. APL Bioeng. 2018;2(4):046103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Kim SI, Matsumoto T, Kagawa H, Nakamura M, Hirohata R, Ueno A, et al. Microhomology-assisted scarless genome editing in human iPSCs. Nat Commun. 2018;9(1):939.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Turan S, Farruggio AP, Srifa W, Day JW, Calos MP. Precise correction of disease mutations in induced pluripotent stem cells derived from patients with limb girdle muscular dystrophy. Mol Ther. 2016;24(4):685–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Howden SE, Maufort JP, Duffin BM, Elefanty AG, Stanley EG, Thomson JA. Simultaneous reprogramming and gene correction of patient fibroblasts. Stem Cell Reports. 2015;5(6):1109–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Zhu Z, Gonzalez F, Huangfu D. The iCRISPR platform for rapid genome editing in human pluripotent stem cells. Methods Enzymol. 2014;546:215–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337(6099):1190–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Kwart D, Paquet D, Teo S, Tessier-Lavigne M. Precise and efficient scarless genome editing in stem cells using CORRECT. Nat Protoc. 2017;12(2):329–54.

    Article  PubMed  CAS  Google Scholar 

  225. Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell. 2017;170(3):522–533.e515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Schatoff EM, Zafra MP, Dow LE. Base editing the mammalian genome. Methods. 2019;164–165:100–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  227. Komor AC, Badran AH, Liu DR. Editing the genome without double-stranded DNA breaks. ACS Chem Biol. 2018;13(2):383–8.

    Article  PubMed  CAS  Google Scholar 

  228. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Kim YB, Komor AC, Levy JM, Packer MS, Zhao KT, Liu DR. Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nat Biotechnol. 2017;35(4):371–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Rees HA, Komor AC, Yeh WH, Caetano-Lopes J, Warman M, Edge ASB, et al. Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat Commun. 2017;8:15790.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Zafra MP, Schatoff EM, Katti A, Foronda M, Breinig M, Schweitzer AY, et al. Optimized base editors enable efficient editing in cells, organoids and mice. Nat Biotechnol. 2018;36(9):888–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Li Q, Li Y, Yang S, Huang S, Yan M, Ding Y, et al. CRISPR-Cas9-mediated base-editing screening in mice identifies DND1 amino acids that are critical for primordial germ cell development. Nat Cell Biol. 2018;20(11):1315–25.

    Article  PubMed  CAS  Google Scholar 

  234. Kim K, Ryu SM, Kim ST, Baek G, Kim D, Lim K, et al. Highly efficient RNA-guided base editing in mouse embryos. Nat Biotechnol. 2017;35(5):435–7.

    Article  PubMed  CAS  Google Scholar 

  235. Liu Z, Chen M, Shan H, Chen S, Xu Y, Song Y, et al. Expanded targeting scope and enhanced base editing efficiency in rabbit using optimized xCas9(3.7). Cell Mol Life Sci. 2019;76(20):4155–64.

    Article  PubMed  CAS  Google Scholar 

  236. Liu Z, Chen S, Shan H, Zhang Q, Chen M, Lai L, et al. Efficient and precise base editing in rabbits using human APOBEC3A-nCas9 fusions. Cell Discov. 2019;5:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Xie J, Ge W, Li N, Liu Q, Chen F, Yang X, et al. Efficient base editing for multiple genes and loci in pigs using base editors. Nat Commun. 2019;10(1):2852.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Chadwick AC, Wang X, Musunuru K. In vivo base editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol. 2017;37(9):1741–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Yuan J, Ma Y, Huang T, Chen Y, Peng Y, Li B, et al. Genetic modulation of RNA splicing with a CRISPR-guided cytidine deaminase. Mol Cell. 2018;72(2):380–394.e387.

    Article  PubMed  CAS  Google Scholar 

  240. Chang YJ, Xu CL, Cui X, Bassuk AG, Mahajan VB, Tsai YT, et al. CRISPR base editing in induced pluripotent stem cells. Methods Mol Biol. 2019;2045:337–46.

    Article  PubMed  CAS  Google Scholar 

  241. Standage-Beier K, Tekel SJ, Brookhouser N, Schwarz G, Nguyen T, Wang X, et al. A transient reporter for editing enrichment (TREE) in human cells. Nucleic Acids Res. 2019;47(19):e120.

    Article  PubMed  PubMed Central  Google Scholar 

  242. Osborn MJ, Newby GA, McElroy AN, Knipping F, Nielsen SC, Riddle MJ, et al. Base editor correction of COL7A1 in recessive dystrophic epidermolysis bullosa patient-derived fibroblasts and iPSCs. J Invest Dermatol. 2019;140:338.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  243. Liang P, Ding C, Sun H, Xie X, Xu Y, Zhang X, et al. Correction of beta-thalassemia mutant by base editor in human embryos. Protein Cell. 2017;8(11):811–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Yeh WH, Chiang H, Rees HA, Edge ASB, Liu DR. In vivo base editing of post-mitotic sensory cells. Nat Commun. 2018;9(1):2184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  245. Zuo E, Sun Y, Wei W, Yuan T, Ying W, Sun H, et al. Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science. 2019;364(6437):289–92.

    PubMed  CAS  PubMed Central  Google Scholar 

  246. • Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576(7785):149–57. Description of prime editing, a new "search and replace" CRISPR/Cas9-based technology that offers similar editing efficiency as base editing, but the diverse editing capability of traditional CRISPR/Cas9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  247. Margolin JF, Friedman JR, Meyer WK, Vissing H, Thiesen HJ, Rauscher FJ 3rd. Kruppel-associated boxes are potent transcriptional repression domains. Proc Natl Acad Sci U S A. 1994;91(10):4509–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Groner AC, Meylan S, Ciuffi A, Zangger N, Ambrosini G, Denervaud N, et al. KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading. PLoS Genet. 2010;6(3):e1000869.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  249. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152(5):1173–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  250. Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154(2):442–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  251. Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH, et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell. 2014;159(3):647–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Cheng AW, Wang H, Yang H, Shi L, Katz Y, Theunissen TW, et al. Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res. 2013;23(10):1163–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  253. Chavez A, Scheiman J, Vora S, Pruitt BW, Tuttle M, PRI E, et al. Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015;12(4):326–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Tanenbaum ME, Gilbert LA, Qi LS, Weissman JS, Vale RD. A protein-tagging system for signal amplification in gene expression and fluorescence imaging. Cell. 2014;159(3):635–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  255. Hilton IB, D'Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  256. Perez-Pinera P, Kocak DD, Vockley CM, Adler AF, Kabadi AM, Polstein LR, et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat Methods. 2013;10(10):973–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. Liu Y, Yu C, Daley TP, Wang F, Cao WS, Bhate S, et al. CRISPR Activation screens systematically identify factors that drive neuronal fate and reprogramming. Cell Stem Cell. 2018;23(5):758–771.e758.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  258. Kurata M, Yamamoto K, Moriarity BS, Kitagawa M, Largaespada DA. CRISPR/Cas9 library screening for drug target discovery. J Hum Genet. 2018;63(2):179–86.

    Article  PubMed  CAS  Google Scholar 

  259. Bester AC, Lee JD, Chavez A, Lee YR, Nachmani D, Vora S, et al. An integrated genome-wide CRISPRa approach to functionalize lncRNAs in drug resistance. Cell. 2018;173(3):649–664.e620.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  260. Gao X, Tsang JC, Gaba F, Wu D, Lu L, Liu P. Comparison of TALE designer transcription factors and the CRISPR/dCas9 in regulation of gene expression by targeting enhancers. Nucleic Acids Res. 2014;42(20):e155.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Weltner J, Balboa D, Katayama S, Bespalov M, Krjutskov K, Jouhilahti EM, et al. Human pluripotent reprogramming with CRISPR activators. Nat Commun. 2018;9(1):2643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  262. Ovchinnikov DA, Korn O, Virshup I, Wells CA, Wolvetang EJ. The Impact of APP on Alzheimer-like Pathogenesis and Gene Expression in Down Syndrome iPSC-Derived Neurons. Stem Cell Reports. 2018;11(1):32–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Guo J, Ma D, Huang R, Ming J, Ye M, Kee K, et al. An inducible CRISPR-ON system for controllable gene activation in human pluripotent stem cells. Protein Cell. 2017;8(5):379–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Savell KE, Bach SV, Zipperly ME, Revanna JS, Goska NA, Tuscher JJ, et al. A neuron-optimized CRISPR/dCas9 activation system for robust and specific gene regulation. eNeuro. 2019;6(1):ENEURO.0495-18.2019.

    Article  PubMed  PubMed Central  Google Scholar 

  265. Baumann V, Stricker SH. Seeking fate-CRISPRa screens reveal new neural lineage and reprogramming factors. Stem Cell Investig. 2019;6:30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  266. Yang J, Rajan SS, Friedrich MJ, Lan G, Zou X, Ponstingl H, et al. Genome-scale CRISPRa screen identifies novel factors for cellular reprogramming. Stem Cell Reports. 2019;12(4):757–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  267. Butler AA, Johnston DR, Kaur S, Lubin FD. Long noncoding RNA NEAT1 mediates neuronal histone methylation and age-related memory impairment. Sci Signal. 2019;12(588):eaaw9277.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  268. Lau CH, Ho JW, Lo PK, Tin C. Targeted transgene activation in the brain tissue by systemic delivery of engineered AAV1 expressing CRISPRa. Mol Ther Nucleic Acids. 2019;16:637–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  269. Tsai PH, Chien Y, Wang ML, Hsu CH, Laurent B, Chou SJ, et al. Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network. Nucleic Acids Res. 2019;47(19):10115–33.

    Article  PubMed  PubMed Central  Google Scholar 

  270. Genga RMJ, Kernfeld EM, Parsi KM, Parsons TJ, Ziller MJ, Maehr R. Single-cell RNA-sequencing-based CRISPRi screening resolves molecular drivers of early human endoderm development. Cell Rep. 2019;27(3):708–718.e710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  271. Eskildsen TV, Ayoubi S, Thomassen M, Burton M, Mandegar MA, Conklin BR, et al. MESP1 knock-down in human iPSC attenuates early vascular progenitor cell differentiation after completed primitive streak specification. Dev Biol. 2019;445(1):1–7.

    Article  PubMed  CAS  Google Scholar 

  272. Mandegar MA, Huebsch N, Frolov EB, Shin E, Truong A, Olvera MP, et al. CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs. Cell Stem Cell. 2016;18(4):541–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  273. Huang YA, Zhou B, Wernig M, Sudhof TC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and abeta secretion. Cell. 2017;168(3):427–441.e421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  274. Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D, et al. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science. 2017;355(6320):aah7111.

    Article  PubMed  CAS  Google Scholar 

  275. Liu SJ, Nowakowski TJ, Pollen AA, Lui JH, Horlbeck MA, Attenello FJ, et al. Single-cell analysis of long non-coding RNAs in the developing human neocortex. Genome Biol. 2016;17:67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  276. Heman-Ackah SM, Bassett AR, Wood MJ. Precision modulation of neurodegenerative disease-related gene expression in human iPSC-derived Neurons. Sci Rep. 2016;6:28420.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  277. Tian R, Gachechiladze MA, Ludwig CH, Laurie MT, Hong JY, Nathaniel D, et al. CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron. 2019;104(2):239–255.e212.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  278. Teshigawara R, Cho J, Kameda M, Tada T. Mechanism of human somatic reprogramming to iPS cell. Lab Investig. 2017;97(10):1152–7.

    Article  PubMed  CAS  Google Scholar 

  279. Hoffman GE, Schrode N, Flaherty E, Brennand KJ. New considerations for hiPSC-based models of neuropsychiatric disorders. Mol Psychiatry. 2019;24(1):49–66.

    Article  PubMed  CAS  Google Scholar 

  280. Cheung AY, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, et al. Isolation of MECP2-null Rett syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet. 2011;20(11):2103–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  281. Ananiev G, Williams EC, Li H, Chang Q. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One. 2011;6(9):e25255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  282. Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, et al. Signaling defects in iPSC-derived fragile X premutation neurons. Hum Mol Genet. 2012;21(17):3795–805.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  283. Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, et al. iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells Dev. 2014;23(15):1777–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  284. Martinez RA, Stein JL, Krostag AR, Nelson AM, Marken JS, Menon V, et al. Genome engineering of isogenic human ES cells to model autism disorders. Nucleic Acids Res. 2015;43(10):e65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  285. 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;8:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  286. Srikanth P, Han K, Callahan DG, Makovkina E, Muratore CR, Lalli MA, et al. Genomic DISC1 disruption in hiPSCs alters Wnt signaling and neural cell fate. Cell Rep. 2015;12(9):1414–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  287. Pak C, Danko T, Zhang Y, Aoto J, Anderson G, Maxeiner S, et al. Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell. 2015;17(3):316–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  288. Wang P, Lin M, Pedrosa E, Hrabovsky A, Zhang Z, Guo W, et al. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol Autism. 2015;6:55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  289. 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(11):1350–65.

    Article  PubMed  CAS  Google Scholar 

  290. Murai K, Sun G, Ye P, Tian E, Yang S, Cui Q, et al. The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun. 2016;7:10965.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  291. Nott A, Cheng J, Gao F, Lin YT, Gjoneska E, Ko T, et al. Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat Neurosci. 2016;19(11):1497–505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  292. Tcw J, Carvalho CMB, Yuan B, Gu S, Altheimer AN, McCarthy S, et al. Divergent levels of marker chromosomes in an hiPSC-based model of psychosis. Stem Cell Reports. 2017;8(3):519–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  293. Wang P, Mokhtari R, Pedrosa E, Kirschenbaum M, Bayrak C, Zheng D, et al. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells. Mol Autism. 2017;8:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  294. Kathuria A, Nowosiad P, Jagasia R, Aigner S, Taylor RD, Andreae LC, et al. Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development. Mol Psychiatry. 2018;23(3):735–46.

    Article  PubMed  CAS  Google Scholar 

  295. Srikanth P, Lagomarsino VN, Muratore CR, Ryu SC, He A, Taylor WM, et al. Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids. Transl Psychiatry. 2018;8(1):77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  296. Mellios N, Feldman DA, Sheridan SD, Ip JPK, Kwok S, Amoah SK, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry. 2018;23(4):1051–65.

    Article  PubMed  CAS  Google Scholar 

  297. Barnes J, Salas F, Mokhtari R, Dolstra H, Pedrosa E, Lachman HM. Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells. Mol Autism. 2018;9:44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  298. Deneault E, White SH, Rodrigues DC, Ross PJ, Faheem M, Zaslavsky K, et al. Complete disruption of autism-susceptibility genes by gene editing predominantly reduces functional connectivity of isogenic human neurons. Stem Cell Reports. 2018;11(5):1211–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  299. Deneault E, Faheem M, White SH, Rodrigues DC, Sun S, Wei W, et al. CNTN5(−)(/+)or EHMT2(−)(/+)human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks. Elife. 2019;8:e40092.

    Article  PubMed  PubMed Central  Google Scholar 

  300. Zaslavsky K, Zhang WB, McCready FP, Rodrigues DC, Deneault E, Loo C, et al. SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons. Nat Neurosci. 2019;22(4):556–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  301. Bentea E, Depasquale EAK, O'Donovan SM, Sullivan CR, Simmons M, Meador-Woodruff JH, et al. Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia. Mol Omics. 2019;15(3):173–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  302. Kizner V, Naujock M, Fischer S, Jager S, Reich S, Schlotthauer I, et al. CRISPR/Cas9-mediated knockout of the neuropsychiatric risk gene KCTD13 causes developmental deficits in human cortical neurons derived from induced pluripotent stem cells. Mol Neurobiol. 2019;57:616–34.

    Article  PubMed  CAS  Google Scholar 

  303. Marro SG, Chanda S, Yang N, Janas JA, Valperga G, Trotter J, et al. Neuroligin-4 regulates excitatory synaptic transmission in human neurons. Neuron. 2019;103(4):617–626.e616.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  304. Ishii T, Ishikawa M, Fujimori K, Maeda T, Kushima I, Arioka Y, et al. In vitro modeling of the bipolar disorder and schizophrenia using patient-derived induced pluripotent stem cells with copy number variations of PCDH15 and RELN. eNeuro. 2019;6(5):ENEURO.0403-18.2019.

    Article  PubMed  PubMed Central  Google Scholar 

  305. Li J, Ryan SK, Deboer E, Cook K, Fitzgerald S, Lachman HM, et al. Mitochondrial deficits in human iPSC-derived neurons from patients with 22q11.2 deletion syndrome and schizophrenia. Transl Psychiatry. 2019;9(1):302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  306. • Hoekstra SD, Stringer S, Heine VM, Posthuma D. Genetically-informed patient selection for iPSC studies of complex diseases may aid in reducing cellular heterogeneity. Front Cell Neurosci. 2017;11:164. A discussion on how to strategically choose patient iPSC lines to utilize for studying complex disease in order to reduce noise associated with differences in genetic risk.

    Article  PubMed  PubMed Central  Google Scholar 

  307. Johnstone M, Hillary RF, St Clair D. Stem cells to inform the neurobiology of mental illness. Curr Top Behav Neurosci. 2018;40:13–43.

    Article  PubMed  Google Scholar 

  308. Colpo GD, Stertz L, Diniz BS, Teixeira AL. Potential use of stem cells in mood disorders. Adv Exp Med Biol. 2018;1089:87–96.

    Article  PubMed  CAS  Google Scholar 

  309. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry. 2015;20(3):361–8.

    Article  PubMed  CAS  Google Scholar 

  310. Robicsek O, Karry R, Petit I, Salman-Kesner N, Muller FJ, 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(10):1067–76.

    Article  PubMed  CAS  Google Scholar 

  311. Toyoshima M, Akamatsu W, Okada Y, Ohnishi T, Balan S, Hisano Y, et al. Analysis of induced pluripotent stem cells carrying 22q11.2 deletion. Transl Psychiatry. 2016;6(11):e934.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  312. Deans PJM, Raval P, Sellers KJ, Gatford NJF, Halai S, Duarte RRR, et al. Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure. Biol Psychiatry. 2017;82(1):49–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  313. Topol A, Zhu S, Tran N, Simone A, Fang G, Brennand KJ. Altered WNT signaling in human induced pluripotent stem cell neural progenitor cells derived from four schizophrenia patients. Biol Psychiatry. 2015;78(6):e29–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  314. Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med. 2011;17(12):1657–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  315. 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(7):569–78.

    Article  PubMed  Google Scholar 

  316. • Marchetto MC, 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(4):527–39. This is the earliest study where ASD (syndromic- Rett syndrome) iPSCs were generated and compared to controls.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  317. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503(7475):267–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  318. Ebrahimi-Fakhari D, Saffari A, Wahlster L, Di Nardo A, Turner D, Lewis TL Jr, et al. Impaired mitochondrial dynamics and mitophagy in neuronal models of tuberous sclerosis complex. Cell Rep. 2016;17(4):1053–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  319. Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry. 2018;23(6):1453–65.

    Article  PubMed  CAS  Google Scholar 

  320. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, 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(6):703–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  321. Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, et al. Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry. 2015;20(5):573–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  322. • Chen HM, De Long CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, et al. Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry. 2014;4:e375. This is the earliest study where bipolar patient iPSCs were generated and compared to controls.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  323. Lin M, Pedrosa E, Shah A, Hrabovsky A, Maqbool S, Zheng D, et al. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS One. 2011;6(9):e23356.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  324. Vizlin-Hodzic D, Zhai Q, Illes S, Sodersten K, Truve K, Parris TZ, et al. Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages. Transl Psychiatry. 2017;7(1):e1010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  325. Hartley BJ, Tran N, Ladran I, Reggio K, Brennand KJ. Dopaminergic differentiation of schizophrenia hiPSCs. Mol Psychiatry. 2015;20(5):549–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  326. Russo FB, Cugola FR, Fernandes IR, Pignatari GC, Beltrao-Braga PC. Induced pluripotent stem cells for modeling neurological disorders. World J Transplant. 2015;5(4):209–21.

    Article  PubMed  PubMed Central  Google Scholar 

  327. Prilutsky D, Palmer NP, Smedemark-Margulies N, Schlaeger TM, Margulies DM, Kohane IS. iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls. Trends Mol Med. 2014;20(2):91–104.

    Article  PubMed  CAS  Google Scholar 

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Funding

This work was supported by NIH grants T32GM07814, R01MH113215, P50MH094268, and R01MH106522. Figures were created with BioRender.com

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Author notes

  1. Debamitra Das, Kyra Feuer, and Marah Wahbeh contributed equally

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Debamitra Das

  2. Predoctoral Training Program in Human Genetics, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Kyra Feuer & Marah Wahbeh

  3. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Kyra Feuer, Marah Wahbeh & Dimitrios Avramopoulos

  4. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Dimitrios Avramopoulos

Authors
  1. Debamitra Das
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  2. Kyra Feuer
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  3. Marah Wahbeh
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  4. Dimitrios Avramopoulos
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Correspondence to Dimitrios Avramopoulos.

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Debamitra Das, Kyra Feuer, Marah Wahbeh, and Dimitrios Avramopoulos each declare no potential conflicts of interest.

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Das, D., Feuer, K., Wahbeh, M. et al. Modeling Psychiatric Disorder Biology with Stem Cells. Curr Psychiatry Rep 22, 24 (2020). https://doi.org/10.1007/s11920-020-01148-1

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  • DOI: https://doi.org/10.1007/s11920-020-01148-1

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