Modeling neuropsychiatric disorders using human induced pluripotent stem cells
Meiyan Wang1,2, Lei Zhang1, Fred H. Gage1()
1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, CA 92037, USA 2. Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA
Neuropsychiatric disorders are complex disorders characterized by heterogeneous genetic variations, variable symptoms, and widespread changes in anatomical pathology. In the context of neuropsychiatric disorders, limited access to relevant tissue types presents challenges for understanding disease etiology and developing effective treatments. Induced pluripotent stem cells (iPSCs) reprogrammed from patient somatic cells offer an opportunity to recapitulate disease development in relevant cell types, and they provide novel approaches for understanding disease mechanisms and for development of effective treatments. Here we review recent progress and challenges in differentiation paradigms for generating disease-relevant cells and recent studies of neuropsychiatric disorders using human pluripotent stem cell (hPSC) models where cellular phenotypes linked to disease have been reported. The use of iPSC-based disease models holds great promise for understanding disease mechanisms and supporting discovery of effective treatments.
. [J]. Protein & Cell, 2020, 11(1): 45-59.
Meiyan Wang, Lei Zhang, Fred H. Gage. Modeling neuropsychiatric disorders using human induced pluripotent stem cells. Protein Cell, 2020, 11(1): 45-59.
EM Abud, RN Ramirez, ES Martinez, LM Healy, CHH Nguyen, SA Newman, AV Yeromin, VM Scarfone, SE Marsh, C Fimbreset al.(2017) iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94(278–293):e279 https://doi.org/10.1016/j.neuron.2017.03.042
2
A Amiri, G Coppola, S Scuderi, F Wu, T Roychowdhury, F Liu, S Pochareddy, Y Shin, A Safi, L Songet al. (2018) Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362:eaat6720 https://doi.org/10.1126/science.aat6720
3
JA Bagley, D Reumann, S Bian, J Levi-Strauss, JA Knoblich (2017) Fused cerebral organoids model interactions between brain regions. Nat Methods 14:743–751 https://doi.org/10.1038/nmeth.4304
4
S Bavamian, N Mellios, J Lalonde, DM Fass, J Wang, SD Sheridan, JM Madison, F Zhou, EH Rueckert, D Barkeret al. (2015) Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry 20:573–584 https://doi.org/10.1038/mp.2014.176
5
M Bershteyn, TJ Nowakowski, AA Pollen, E Di Lullo, A Nene, A Wynshaw-Boris, AR Kriegstein (2017) Human iPSC-derived cerebral organoids model cellular features of lissencephaly and reveal prolonged mitosis of outer radial glia. Cell Stem Cell 20 (435–449):e434 https://doi.org/10.1016/j.stem.2016.12.007
6
D Bipolar, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address, d.r.v.e., Bipolar, D., and Schizophrenia Working Group of the Psychiatric C Genomics, (2018) Genomic dissection of bipolar disorder and schizophrenia, including 28 SUBPHENOTYPES. Cell 173:1705e1716–1715e1716
7
F Birey, J Andersen, CD Makinson, S Islam, W Wei, N Huber, HC Fan, KRC Metzler, G Panagiotakos, N Thomet al. (2017) Assembly of functionally integrated human forebrain spheroids. Nature 545:54–59 https://doi.org/10.1038/nature22330
8
K Brennand, JN Savas, Y Kim, N Tran, A Simone, K Hashimoto-Torii, KG Beaumont, HJ Kim, A Topol, I Ladranet al. (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20:361–368 https://doi.org/10.1038/mp.2014.22
9
KJ Brennand, A Simone, J Jou, C Gelboin-Burkhart, N Tran, S Sangar, Y Li, Y Mu, G Chen, D Yuet al. (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473:221–225 https://doi.org/10.1038/nature09915
10
M Bundo, M Toyoshima, Y Okada, W Akamatsu, J Ueda, T Nemoto-Miyauchi, F Sunaga, M Toritsuka, D Ikawa, A Kakitaet al. (2014) Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron 81:306–313 https://doi.org/10.1016/j.neuron.2013.10.053
11
O Butovsky, MP Jedrychowski, CS Moore, R Cialic, AJ Lanser, G Gabriely, T Koeglsperger, B Dake, PM Wu, CE Doykanet al. (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143 https://doi.org/10.1038/nn.3599
12
SM Chambers, CA Fasano, EP Papapetrou, M Tomishima, M Sadelain, L Studer (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27:275–280 https://doi.org/10.1038/nbt.1529
13
L Ciani, PC Salinas (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–362 https://doi.org/10.1038/nrn1665
14
MA Cirillo, LJ Seidman (2003) Verbal declarative memory dysfunction in schizophrenia: from clinical assessment to genetics and brain mechanisms. Neuropsychol Rev 13:43–77 https://doi.org/10.1023/A:1023870821631
15
S Darmanis, SA Sloan, Y Zhang, M Enge, C Caneda, LM Shuer, MG Hayden Gephart, BA Barres, SR Quake (2015) A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A 112:7285–7290 https://doi.org/10.1073/pnas.1507125112
16
C Dehay, H Kennedy, KS Kosik (2015) The outer subventricular zone and primate-specific cortical complexification. Neuron 85:683–694 https://doi.org/10.1016/j.neuron.2014.12.060
17
A Deshpande, S Yadav, DQ Dao, ZY Wu, KC Hokanson, MK Cahill, AP Wiita, YN Jan, EM Ullian, LA Weiss (2017) Cellular phenotypes in human iPSC-derived neurons from a genetic model of autism spectrum disorder. Cell Rep 21:2678–2687 https://doi.org/10.1016/j.celrep.2017.11.037
18
E Di Lullo, AR Kriegstein (2017) The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci 18:573–584 https://doi.org/10.1038/nrn.2017.107
19
T Edlund, TM Jessell (1999) Progression from extrinsic to intrinsic signalling in cell fate specification: a view from the nervous system. Cell 96:211–224 https://doi.org/10.1016/S0092-8674(00)80561-9
20
M Eiraku, K Watanabe, M Matsuo-Takasaki, M Kawada, S Yonemura, M Matsumura, T Wataya, A Nishiyama, K Muguruma, Y Sasai (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3:519–532 https://doi.org/10.1016/j.stem.2008.09.002
I Espuny-Camacho, KA Michelsen, D Gall, D Linaro, A Hasche, J Bonnefont, C Bali, D Orduz, A Bilheu, A Herpoelet al.(2013) Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77:440–456 https://doi.org/10.1016/j.neuron.2012.12.011
23
I Feinberg (1982) Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 17:319–334 https://doi.org/10.1016/0022-3956(82)90038-3
24
R Freedman, D Goldowitz (2010) Studies on the hippocampal formation: From basic development to clinical applications: Studies on schizophrenia. Prog Neurobiol 90:263–275 https://doi.org/10.1016/j.pneurobio.2009.10.008
25
M Fuccillo, AL Joyner, G Fishell (2006) Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7:772–783 https://doi.org/10.1038/nrn1990
26
J Galceran, EM Miyashita-Lin, E Devaney, JL Rubenstein, R Grosschedl (2000) Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1. Development 127:469–482
27
N Gaspard, T Bouschet, R Hourez, J Dimidschstein, G Naeije, J van den Ameele, I Espuny-Camacho, A Herpoel, L Passante, SN Schiffmannet al. (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455:351–357 https://doi.org/10.1038/nature07287
28
F Ginhoux, M Greter, M Leboeuf, S Nandi, P See, S Gokhan, MF Mehler, SJ Conway, LG Ng, ER Stanleyet al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845 https://doi.org/10.1126/science.1194637
29
A Gore, Z Li, HL Fung, JE Young, S Agarwal, J Antosiewicz-Bourget, I Canto, A Giorgetti, MA Israel, E Kiskiniset al. (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67 https://doi.org/10.1038/nature09805
30
M Greter, I Lelios, P Pelczar, G Hoeffel, J Price, M Leboeuf, TM Kundig, K Frei , F Ginhoux, M Meradet al. (2012) Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37:1050–1060 https://doi.org/10.1016/j.immuni.2012.11.001
31
K Griesi-Oliveira, A Acab, AR Gupta, DY Sunaga, T Chailangkarn, X Nicol, Y Nunez, MF Walker, JD Murdoch, SJ Sanderset al. (2015) Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 20:1350–1365 https://doi.org/10.1038/mp.2014.141
32
J Grove, S Ripke, TD Als, M Mattheisen, RK Walters, H Won, J Pallesen, E Agerbo, OA Andreassen, R Anneyet al. (2019) Identification of common genetic risk variants for autism spectrum disorder. Nat Genet 51:431–444 https://doi.org/10.1038/s41588-019-0344-8
33
F Guillemot, C Zimmer (2011) From cradle to grave: the multiple roles of fibroblast growth factors in neural development. Neuron 71:574–588 https://doi.org/10.1016/j.neuron.2011.08.002
34
Y Hakak, JR Walker, C Li, WH Wong, KL Davis, JD Buxbaum, V Haroutunian, AA Fienberg (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A 98:4746–4751 https://doi.org/10.1073/pnas.081071198
35
K Hashimoto-Torii, M Torii, M Fujimoto, A Nakai, R El Fatimy, V Mezger, MJ Ju, S Ishii, SH Chao, KJ Brennandet al. (2014) Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82:560–572 https://doi.org/10.1016/j.neuron.2014.03.002
36
V Hook, KJ Brennand, Y Kim, T Toneff, L Funkelstein, KC Lee, M Ziegler, FH Gage (2014) Human iPSC neurons display activitydependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Rep 3:531–538 https://doi.org/10.1016/j.stemcr.2014.08.001
37
BY Hu, ZW Du, SC Zhang (2009) Differentiation of human oligodendrocytes from pluripotent stem cells. Nat Protoc 4:1614–1622 https://doi.org/10.1038/nprot.2009.186
38
V Iefremova, G Manikakis, O Krefft, A Jabali, K Weynans, R Wilkens, F Marsoner, B Brandl, FJ Muller, P Kochet al. (2017) An organoidbased model of cortical development identifies non-cell-autonomous defects in Wnt signalling contributing to Miller-Dieker syndrome. Cell Rep 19:50–59 https://doi.org/10.1016/j.celrep.2017.03.047
39
J Ji, SH Ng, V Sharma, D Neculai, S Hussein, M Sam, Q Trinh, GM Church, JD McPherson, A Nagyet al.(2012) Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells. Stem Cells 30:435–440 https://doi.org/10.1002/stem.1011
40
J Jo, Y Xiao, AX Sun, E Cukuroglu, HD Tran, J Goke, ZY Tan, TY Saw, CP Tan, H Lokmanet al. (2016) Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 19:248–257 https://doi.org/10.1016/j.stem.2016.07.005
41
JR Jones, L Kong, MGT Hanna, B Hoffman, R Krencik, R Bradley, T Hagemann, J Choi, M Doers, M Duboviset al. (2018) Mutations in GFAP disrupt the distribution and function of organelles in human astrocytes. Cell Rep 25:947–958 https://doi.org/10.1016/j.celrep.2018.09.083
42
T Kadoshima, H Sakaguchi, T Nakano, M Soen, S Ando, M Eiraku, Y Sasai (2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A 110:20284–20289 https://doi.org/10.1073/pnas.1315710110
43
E Kang, X Wang, R Tippner-Hedges, H Ma, CD Folmes, NM Gutierrez, Y Lee, C Van Dyken, R Ahmed, Y Liet al. (2016) Age-related accumulation of somatic mitochondrial DNA mutations in adultderived human iPSCs. Cell Stem Cell 18:625–636 https://doi.org/10.1016/j.stem.2016.02.005
44
HS Keirstead, G Nistor, G Bernal, M Totoiu, F Cloutier, K Sharp, O Steward (2005) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25:4694–4705 https://doi.org/10.1523/JNEUROSCI.0311-05.2005
CL Kerr, BS Letzen, CM Hill, G Agrawal, NV Thakor, JL Sterneckert, JD Gearhart, AH All (2010) Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury. Int J Neurosci 120:305–313 https://doi.org/10.3109/00207450903585290
48
BS Khakh, MV Sofroniew (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952 https://doi.org/10.1038/nn.4043
49
K Kierdorf, D Erny, T Goldmann, V Sander, C Schulz, EG Perdiguero, P Wieghofer, A Heinrich, P Riemke, C Holscheret al. (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280 https://doi.org/10.1038/nn.3318
50
NS Kolomeets, DD Orlovskaya, NA Uranova (2007) Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia. Synapse 61:615–621 https://doi.org/10.1002/syn.20405
51
R Krencik, JP Weick, Y Liu, ZJ Zhang, SC Zhang (2011) Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29:528–534 https://doi.org/10.1038/nbt.1877
52
R Krencik, SC Zhang (2011) Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 6:1710–1717 https://doi.org/10.1038/nprot.2011.405
53
BB Lake, R Ai, GE Kaeser, NS Salathia, YC Yung, R Liu, A Wildberg, D Gao, HL Fung, S Chenet al. (2016) Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 352:1586–1590 https://doi.org/10.1126/science.aaf1204
54
MA Lancaster, M Renner, CA Martin, D Wenzel, LS Bicknell, ME Hurles, T Homfray, JM Penninger, AP Jackson, JA Knoblich (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379 https://doi.org/10.1038/nature12517
55
S Lee, J Hjerling-Leffler, E Zagha, G Fishell, B Rudy (2010) The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 30:16796–16808 https://doi.org/10.1523/JNEUROSCI.1869-10.2010
56
SM Lee, S Tole, E Grove, AP McMahon (2000) A local Wnt-3a signal is required for development of the mammalian hippocampus. Development 127:457–467
57
L Li, E Tian, X Chen, J Chao, J Klein, Q Qu, G Sun, G Sun, Y Huang, CD Wardenet al. (2018) GFAP mutations in astrocytes impair oligodendrocyte progenitor proliferation and myelination in an hiPSC model of alexander disease. Cell Stem Cell 23(239–251): e236 https://doi.org/10.1016/j.stem.2018.07.009
58
W Li, S Ghose, K Gleason, A Begovic, J Perez, J Bartko, S Russo, AD Wagner, L Selemon, CA Tamminga (2015) Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia. Am J Psychiatry 172:373–382 https://doi.org/10.1176/appi.ajp.2014.14010123
59
Y Li, J Muffat, A Omer, I Bosch, MA Lancaster, M Sur, L Gehrke, JA Knoblich, R Jaenisch (2017) Induction of expansion and folding in human cerebral organoids. Cell Stem Cell 20(385–396): e383 https://doi.org/10.1016/j.stem.2016.11.017
60
A Liu, LA Niswander (2005) Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci 6:945–954 https://doi.org/10.1038/nrn1805
61
Y Liu, H Liu, C Sauvey, L Yao, ED Zarnowska, SC Zhang (2013) Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc 8:1670–1679 https://doi.org/10.1038/nprot.2013.106
62
M Maden (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 8:755–765 https://doi.org/10.1038/nrn2212
63
M Madhavan, ZS Nevin, HE Shick, E Garrison, C Clarkson-Paredes, M Karl, BLL Clayton, DC Factor, KC Allan, L Barbaret al.(2018) Induction of myelinating oligodendrocytes in human cortical spheroids. Nat Methods 15:700–706 https://doi.org/10.1038/s41592-018-0081-4
64
JM Madison, F Zhou, A Nigam, A Hussain, DD Barker, R Nehme, K van der Ven, J Hsu, P Wolf, M Fleishmanet al. (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703–717 https://doi.org/10.1038/mp.2015.7
65
AA Mansour, JT Goncalves, CW Bloyd, H Li, S Fernandes, D Quang, S Johnston, SL Parylak, X Jin, FH Gage (2018) An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol 36:432–441 https://doi.org/10.1038/nbt.4127
66
MC Marchetto, H Belinson, Y Tian, BC Freitas, C Fu, K Vadodaria, P Beltrao-Braga, CA Trujillo, APD Mendes, K Padmanabhanet al. (2017) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22:820–835 https://doi.org/10.1038/mp.2016.95
67
MC Marchetto, C Carromeu, A Acab, D Yu, GW Yeo, Y Mu, G Chen, FH Gage, AR Muotri (2010) A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143:527–539 https://doi.org/10.1016/j.cell.2010.10.016
68
J Mariani, G Coppola, P Zhang, A Abyzov, L Provini, L Tomasini, M Amenduni, A Szekely, D Palejev, M Wilsonet al.(2015) FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162:375–390 https://doi.org/10.1016/j.cell.2015.06.034
69
AM Maroof, S Keros, JA Tyson, SW Ying, YM Ganat, FT Merkle, B Liu, A Goulburn, EG Stanley, AG Elefantyet al.(2013) Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12:559–572Mason I (2007) Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat Rev Neurosci 8:583–596 https://doi.org/10.1016/j.stem.2013.04.008
70
C Mayer, C Hafemeister, RC Bandler, R Machold, R Batista Brito, X Jaglin, K Allaway, A Butler, G Fishell, R Satija (2018) Developmental diversification of cortical inhibitory interneurons. Nature 555:457–462 https://doi.org/10.1038/nature25999
71
J Mertens, MC Marchetto, C Bardy, FH Gage (2016) Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci 17:424–437 https://doi.org/10.1038/nrn.2016.46
72
J Mertens, QW Wang, Y Kim, DX Yu, S Pham, B Yang, Y Zheng, KE Diffenderfer, J Zhang, S Soltaniet al. (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527:95–99 https://doi.org/10.1038/nature15526
G Miyoshi, J Hjerling-Leffler, T Karayannis, VH Sousa, SJ Butt, J Battiste, JE Johnson, RP Machold, G Fishell (2010) Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J Neurosci 30:1582–1594 https://doi.org/10.1523/JNEUROSCI.4515-09.2010
75
SJ Morrison, SE Perez, Z Qiao, JM Verdi, C Hicks, G Weinmaster, DJ Anderson (2000) Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101:499–510 https://doi.org/10.1016/S0092-8674(00)80860-0
76
J Muffat, Y Li, B Yuan, M Mitalipova, A Omer, S Corcoran, G Bakiasi, LH Tsai, P Aubourg, RM Ransohoffet al. (2016) Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 22:1358–1367 https://doi.org/10.1038/nm.4189
77
K Muguruma, A Nishiyama, H Kawakami, K Hashimoto, Y Sasai (2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep 10:537–550 https://doi.org/10.1016/j.celrep.2014.12.051
78
I Munoz-Sanjuan, AH Brivanlou (2002) Neural induction, the default model and embryonic stem cells. Nat Rev Neurosci 3:271–280 https://doi.org/10.1038/nrn786
79
K Murai, G Sun, P Ye, E Tian, S Yang, Q Cui, G Sun, D Trinh, O Sun, T Honget al. (2016) The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun 7:10965 https://doi.org/10.1038/ncomms10965
EJ Nestler, SE Hyman (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169 https://doi.org/10.1038/nn.2647
82
CR Nicholas, J Chen, Y Tang, DG Southwell, N Chalmers, D Vogt, CM Arnold, YJ Chen, EG Stanley, AG Elefantyet al. (2013) Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12:573–586 https://doi.org/10.1016/j.stem.2013.04.005
83
GI Nistor, MO Totoiu, N Haque, MK Carpenter, HS Keirstead (2005) Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49:385–396 https://doi.org/10.1002/glia.20127
84
H Pandya, MJ Shen, DM Ichikawa, AB Sedlock, Y Choi, KR Johnson, G Kim, MA Brown, AG Elkahloun, D Maricet al. (2017) Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci 20:753–759 https://doi.org/10.1038/nn.4534
85
AM Pasca, SA Sloan, LE Clarke, Y Tian, CD Makinson, N Huber, CH Kim, JY Park, NA O’Rourke, KD Nguyenet al.(2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12:671–678 https://doi.org/10.1038/nmeth.3415
SP Pasca, T Portmann, I Voineagu, M Yazawa, A Shcheglovitov, AM Pasca, B Cord, TD Palmer, S Chikahisa, S Nishinoet al. (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17:1657–1662 https://doi.org/10.1038/nm.2576
89
J Piao, T Major, G Auyeung, E Policarpio, J Menon, L Droms, P Gutin, K Uryu, J Tchieu, D Souletet al. (2015) Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell 16:198–210 https://doi.org/10.1016/j.stem.2015.01.004
90
X Qian, HN Nguyen, MM Song, C Hadiono, SC Ogden, C Hammack, B Yao, GR Hamersky, F Jacob, C Zhonget al. (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165:1238–1254 https://doi.org/10.1016/j.cell.2016.04.032
91
G Quadrato, T Nguyen, EZ Macosko, JL Sherwood, S Min Yang, DR Berger, N Maria, J Scholvin, M Goldman, JP Kinneyet al. (2017) Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545:48–53 https://doi.org/10.1038/nature22047
92
R Rasetti, VS Mattay, MG White, F Sambataro, JE Podell, B Zoltick, Q Chen, KF Berman, JH Callicott, DR Weinberger (2014) Altered hippocampal-parahippocampal function during stimulus encoding: a potential indicator of genetic liability for schizophrenia. JAMA Psychiatry 71:236–247 https://doi.org/10.1001/jamapsychiatry.2013.3911
93
S Ricciardi, F Ungaro, M Hambrock, N Rademacher, G Stefanelli, D Brambilla, A Sessa, C Magagnotti, A Bachi, E Giardaet al. (2012) CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol 14:911–923 https://doi.org/10.1038/ncb2566
94
GMC Rodrigues, T Gaj, MM Adil, J Wahba, AT Rao, FK Lorbeer, RU Kulkarni, MM Diogo, JMS Cabral, EW Milleret al. (2017) Defined and scalable differentiation of human oligodendrocyte precursors from pluripotent stem cells in a 3D culture system. Stem Cell Rep 8:1770–1783 https://doi.org/10.1016/j.stemcr.2017.04.027
95
H Sakaguchi, T Kadoshima, M Soen, N Narii, Y Ishida, M Ohgushi, J Takahashi, M Eiraku, Y Sasai (2015) Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun 6:8896 https://doi.org/10.1038/ncomms9896
96
R Santos, KC Vadodaria, BN Jaeger, A Mei, S Lefcochilos-Fogelquist, APD Mendes, G Erikson, M Shokhirev, L Randolph-Moore, C Fredlenderet al. (2017) Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Rep 8:1757–1769 https://doi.org/10.1016/j.stemcr.2017.05.011
97
A Sarkar, A Mei, ACM Paquola, S Stern, C Bardy, JR Klug, S Kim, N Neshat, HJ Kim, M Kuet al. (2018) Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro. Cell Stem Cell 22(684–697): e689 https://doi.org/10.1016/j.stem.2018.04.009
98
ST Schafer, ACM Paquola, S Stern, D Gosselin, M Ku, M Pena, TJM Kuret, M Liyanage, AA Mansour, BN Jaegeret al. (2019) Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat Neurosci 22:243–255 https://doi.org/10.1038/s41593-018-0295-x
99
Schizophrenia Working Group of the Psychiatric C Genomics, (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427 https://doi.org/10.1038/nature13595
100
C Schulz, E Gomez Perdiguero, L Chorro, H Szabo-Rogers, N Cagnard, K Kierdorf, M Prinz, B Wu, SE Jacobsen, JW Pollardet al. (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90 https://doi.org/10.1126/science.1219179
101
CM Sellgren, J Gracias, B Watmuff, JD Biag, JM Thanos, PB Whittredge, T Fu, K Worringer, HE Brown, J Wanget al. (2019) Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci 22:374–385 https://doi.org/10.1038/s41593-018-0334-7
102
Z Shao, H Noh, W Bin Kim, P Ni, C Nguyen, SE Cote, E Noyes, J Zhao, T Parsons, JM Parket al. (2019) Dysregulated protocadherinpathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia. Nat Neurosci 22:229–242 https://doi.org/10.1038/s41593-018-0313-z
103
J Sharp, J Frame, M Siegenthaler, G Nistor, HS Keirstead (2010) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells 28:152–163 https://doi.org/10.1002/stem.245
104
A Shcheglovitov, O Shcheglovitova, M Yazawa, T Portmann, R Shu, V Sebastiano, A Krawisz, W Froehlich, JA Bernstein, JF Hallmayeret al. (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:267–271 https://doi.org/10.1038/nature12618
105
Y Shi, H Inoue, JC Wu, S Yamanaka (2017) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16:115–130 https://doi.org/10.1038/nrd.2016.245
106
Y Shi, P Kirwan, J Smith, HP Robinson, FJ Livesey (2012) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci 15(477–486):S471 https://doi.org/10.1038/nn.3041
107
SA Sloan, S Darmanis, N Huber, TA Khan, F Birey, C Caneda, R Reimer, SR Quake, BA Barres, SP Pasca (2017) Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95(779–790):e776 https://doi.org/10.1016/j.neuron.2017.07.035
108
S Stern, R Santos, MC Marchetto, APD Mendes, GA Rouleau, S Biesmans, QW Wang, J Yao, P Charnay, AG Banget al.(2018) Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry 23:1453–1465 https://doi.org/10.1038/mp.2016.260
K Takahashi, K Tanabe, M Ohnuki, M Narita, T Ichisaka, K Tomoda, S Yamanaka (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872 https://doi.org/10.1016/j.cell.2007.11.019
D Tkachev, ML Mimmack, MM Ryan, M Wayland, T Freeman, PB Jones, M Starkey, MJ Webster, RH Yolken, S Bahn (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–805 https://doi.org/10.1016/S0140-6736(03)14289-4
115
KC Vadodaria, Y Ji, M Skime, A Paquola, T Nelson, D Hall-Flavin, C Fredlender, KJ Heard, Y Deng, AT Leet al. (2019) Serotonininduced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry. https://doi.org/10.1038/s41380-019-0363-y
116
I Voineagu, X Wang, P Johnston, JK Lowe, Y Tian, S Horvath, J Mill, RM Cantor, BJ Blencowe, DH Geschwind (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:380–384 https://doi.org/10.1038/nature10110
117
L Wang, J Xia, J Li, TL Hagemann, JR Jones, E Fraenkel, DA Weitz, SC Zhang, A Messing, MB Feany (2018) Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun 9:1899 https://doi.org/10.1038/s41467-018-04269-7
118
S Wang, J Bates, X Li, S Schanz, D Chandler-Militello, C Levine, N Maherali, L Studer, K Hochedlinger, M Windremet al. (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12:252–264 https://doi.org/10.1016/j.stem.2012.12.002
119
Y Wang, KJ Szretter, W Vermi, S Gilfillan, C Rossini, M Cella, AD Barrow, MS Diamond, M Colonna (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13:753–760 https://doi.org/10.1038/ni.2360
120
K Watanabe, D Kamiya, A Nishiyama, T Katayama, S Nozaki, H Kawasaki, Y Watanabe, K Mizuseki, Y Sasai (2005) Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 8:288–296 https://doi.org/10.1038/nn1402
121
Z Wen, HN Nguyen, Z Guo, MA Lalli, X Wang, Y Su, NS Kim, KJ Yoon, J Shin, C Zhanget al. (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515:414–418 https://doi.org/10.1038/nature13716
RA Wimmer, A Leopoldi, M Aichinger, N Wick, B Hantusch, M Novatchkova, J Taubenschmid, M Hammerle, C Esk, JA Bagleyet al. (2019) Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565:505–510 https://doi.org/10.1038/s41586-018-0858-8
124
MS Windrem, M Osipovitch, Z Liu, J Bates, D Chandler-Militello, L Zou, J Munir, S Schanz, K McCoy, RH Milleret al. (2017) Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 21(195–208):e196 https://doi.org/10.1016/j.stem.2017.06.012
125
CP Wonders, SA Anderson (2006) The origin and specification of cortical interneurons. Nat Rev Neurosci 7:687–696 https://doi.org/10.1038/nrn1954
126
NR Wray, S Ripke, M Mattheisen, M Trzaskowski, EM Byrne, A Abdellaoui, MJ Adams, E Agerbo, TM Air, TMF Andlaueret al. (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet 50:668–681 https://doi.org/10.1038/s41588-018-0090-3
127
Y Xiang, Y Tanaka, B Patterson, YJ Kang, G Govindaiah, N Roselaar, B Cakir, KY Kim, AP Lombroso, SM Hwanget al. (2017) Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21 (383–398):e387 https://doi.org/10.1016/j.stem.2017.07.007
128
R Yamasaki, H Lu, O Butovsky, N Ohno, AM Rietsch, R Cialic, PM Wu, CE Doykan, J Lin, AC Cotleuret al. (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211:1533–1549 https://doi.org/10.1084/jem.20132477
129
N Yang, JB Zuchero, H Ahlenius, S Marro, YH Ng, T Vierbuchen, JS Hawkins, R Geissler, BA Barres, M Wernig (2013) Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol 31:434–439 https://doi.org/10.1038/nbt.2564
130
KJ Yoon, HN Nguyen, G Ursini, F Zhang, NS Kim, Z Wen, G Makri, D Nauen, JH Shin, Y Parket al.(2014) Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15:79–91 https://doi.org/10.1016/j.stem.2014.05.003
131
DX Yu, FP Di Giorgio, J Yao, MC Marchetto, K Brennand, R Wright, A Mei, L McHenry, D Lisuk, JM Grasmicket al. (2014) Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2:295–310 https://doi.org/10.1016/j.stemcr.2014.01.009
132
J Yu, MA Vodyanik, K Smuga-Otto, J Antosiewicz-Bourget, JL Frane, S Tian, J Nie, GA Jonsdottir, V Ruotti, R Stewartet al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920 https://doi.org/10.1126/science.1151526
133
A Zeisel, AB Munoz-Manchado, S Codeluppi, P Lonnerberg, G La Manno, A Jureus, S Marques, H Munguba, L He, C Betsholtzet al. (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347:1138–1142 https://doi.org/10.1126/science.aaa1934
134
Z Zhang, SG Marro, Y Zhang, KL Arendt, C Patzke, B Zhou, T Fair, N Yang, TC Sudhof, M Werniget al. (2018) The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling. Sci Transl Med 10:eaar4338 https://doi.org/10.1126/scitranslmed.aar4338
135
ZN Zhang, BC Freitas, H Qian, J Lux, A Acab, CA Trujillo, RH Herai, VA Nguyen Huu JH Wen, S Joshi-Barret al. (2016) Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. Proc Natl Acad Sci U S A 113:3185–3190 https://doi.org/10.1073/pnas.1521255113
136
D Zhao, M Lin, J Chen, E Pedrosa, A Hrabovsky, HM Fourcade, D Zheng, HM Lachman (2015a) MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11.2 Del. PLoS ONE 10:e0132387 https://doi.org/10.1371/journal.pone.0132387
137
T Zhao, ZN Zhang, Z Rong, Y Xu (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215 https://doi.org/10.1038/nature10135
138
T Zhao, ZN Zhang, PD Westenskow, D Todorova, Z Hu, T Lin, Z Rong, J Kim, J He, M Wanget al. (2015b) Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17:353–359 https://doi.org/10.1016/j.stem.2015.07.021
