Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An update on stem cell biology and engineering for brain development

Abstract

Two recent technologies, induced-pluripotent stem cells (iPSCs) and direct somatic reprogramming, have shown enormous potential for cell-based therapies against intractable diseases such as those that affect the central nervous system. Already, methods that generate most major cell types of the human brain exist. Whether the cell types are directly reprogrammed from human somatic cells or differentiated from an iPSC intermediate, the overview presented here demonstrates how these protocols vary greatly in their efficiencies, purity and maturation of the resulting cells. Possible solutions including micro-RNA switch technologies that purify target cell types are also outlined. Further, an update on the transition from 2D to 3D cultures and current organoid (mini-brain) cultures are reviewed to give the stem cell and developmental engineering communities an up-to-date account of the progress and future perspectives for modeling of central nervous system disease and brain development in vitro.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. Avior Y, Sagi I, Benvenisty N . Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol 2016; 17: 170–182.

    CAS  Article  PubMed  Google Scholar 

  2. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 2012; 482: 216–220.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Evans MJ, Kaufman MH . Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292: 154–156.

    CAS  Article  PubMed  Google Scholar 

  4. Martin GR . Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 1981; 78: 7634–7638.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282: 1145–1147.

    CAS  Article  PubMed  Google Scholar 

  6. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    CAS  Article  PubMed  Google Scholar 

  7. Takahashi K, Okita K, Nakagawa M, Yamanaka S . Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007; 2: 3081–3089.

    CAS  Article  PubMed  Google Scholar 

  8. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M . Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463: 1035–1041.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010; 142: 375–386.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Takahashi K, Yamanaka S . A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016; 17: 183–193.

    CAS  Article  PubMed  Google Scholar 

  11. Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell 2009; 4: 487–492.

    CAS  Article  PubMed  Google Scholar 

  12. Buganim Y, Faddah DA, Jaenisch R . Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 2013; 14: 427–439.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 2000; 28: 31–40.

    CAS  Article  PubMed  Google Scholar 

  14. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 2003; 21: 1200–1207.

    CAS  Article  PubMed  Google Scholar 

  15. Zhang SC, Wernig M, Duncan ID, Brüstle O, Thomson JA . In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 2001; 19: 1129–1133.

    CAS  Article  PubMed  Google Scholar 

  16. Schulz TC, Noggle SA, Palmarini GM, Weiler DA, Lyons IG, Pensa KA et al. Differentiation of human embryonic stem cells to dopaminergic neurons in serum-free suspension culture. Stem Cells 2004; 22: 1218–1238.

    CAS  Article  PubMed  Google Scholar 

  17. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD . Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000; 18: 675–679.

    CAS  Article  PubMed  Google Scholar 

  18. Mertens J, Marchetto MC, Bardy C, Gage FH . Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat Rev Neurosci 2016; 17: 424–437.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Denham M, Dottori M . Neural differentiation of induced pluripotent stem cells. Methods Mol Biol 2011; 793: 99–110.

    CAS  Article  PubMed  Google Scholar 

  20. 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: 275–280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 2008; 3: 519–532.

    CAS  Article  PubMed  Google Scholar 

  22. 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: 771–785.

    CAS  Article  PubMed  Google Scholar 

  23. 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: 477–486.

    CAS  Article  PubMed  Google Scholar 

  24. 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: 1670–1679.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Boyer LF, Campbell B, Larkin S, Mu Y, Gage FH . Dopaminergic differentiation of human pluripotent cells. Curr Protoc Stem Cell Biol 2012; Chapter 1: Unit1H 6.

    PubMed  Google Scholar 

  26. Hu Y, Qu ZY, Cao SY, Li Q, Ma L, Krencik R et al. Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells. J Neurosci Methods 2016; 266: 42–49.

    CAS  Article  PubMed  Google Scholar 

  27. Shimada T, Takai Y, Shinohara K, Yamasaki A, Tominaga-Yoshino K, Ogura A et al. A simplified method to generate serotonergic neurons from mouse embryonic stem and induced pluripotent stem cells. J Neurochem 2012; 122: 81–93.

    CAS  Article  PubMed  Google Scholar 

  28. Lu J, Zhong X, Liu H, Hao L, Huang CT, Sherafat MA et al. Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 2016; 34: 89–94.

    CAS  Article  PubMed  Google Scholar 

  29. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008; 321: 1218–1221.

    CAS  Article  PubMed  Google Scholar 

  30. Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011; 473: 221–225.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Hu BY, Weick JP, Yu J, Ma LX, Zhang XQ, Thomson JA et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci USA 2010; 107: 4335–4340.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 2009; 27: 743–745.

    CAS  Article  PubMed  Google Scholar 

  33. Ohnuki M, Tanabe K, Sutou K, Teramoto I, Sawamura Y, Narita M et al. Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential. Proc Natl Acad Sci USA 2014; 111: 12426–12431.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Kajiwara M, Aoi T, Okita K, Takahashi R, Inoue H, Takayama N et al. Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci USA 2012; 109: 12538–12543.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Koyanagi-Aoi M, Ohnuki M, Takahashi K, Okita K, Noma H, Sawamura Y et al. Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc Natl Acad Sci USA 2013; 110: 20569–20574.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 2013; 112: 523–533.

    CAS  Article  PubMed  Google Scholar 

  37. Bialas AR, Stevens B . Glia: regulating synaptogenesis from multiple directions. Curr Biol 2012; 22: R833–835.

    CAS  Article  PubMed  Google Scholar 

  38. Chung WS, Welsh CA, Barres BA, Stevens B . Do glia drive synaptic and cognitive impairment in disease? Nat Neurosci 2015; 18: 1539–1545.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Krencik R, Weick JP, Liu Y, Zhang ZJ, Zhang SC . Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 2011; 29: 528–534.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Krencik R, Zhang SC . Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 2011; 6: 1710–1717.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Douvaras P, Fossati V . Generation and isolation of oligodendrocyte progenitor cells from human pluripotent stem cells. Nat Protoc 2015; 10: 1143–1154.

    CAS  Article  PubMed  Google Scholar 

  42. Kerman BE, Kim HJ, Padmanabhan K, Mei A, Georges S, Joens MS et al. In vitro myelin formation using embryonic stem cells. Development 2015; 142: 2213–2225.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 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: 55–70.

    CAS  Article  PubMed  Google Scholar 

  44. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 2008; 454: 766–770.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 2011; 25: 2248–2253.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 2013; 13: 691–705.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Lassar AB, Paterson BM, Weintraub H . Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 1986; 47: 649–656.

    CAS  Article  PubMed  Google Scholar 

  48. Davis RL, Weintraub H, Lassar AB . Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51: 987–1000.

    CAS  Article  PubMed  Google Scholar 

  49. Marro S, Pang ZP, Yang N, Tsai MC, Qu K, Chang HY et al. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 2011; 9: 374–382.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 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: 220–223.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D et al. Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell 2011; 146: 359–371.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA et al. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 2011; 9: 113–118.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Han DW, Tapia N, Hermann A, Hemmer K, Höing S, Araúzo-Bravo MJ et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 2012; 10: 465–472.

    CAS  Article  PubMed  Google Scholar 

  54. Liu X, Li F, Stubblefield EA, Blanchard B, Richards TL, Larson GA et al. Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 2012; 22: 321–332.

    CAS  Article  PubMed  Google Scholar 

  55. Liu X, Huang Q, Li F, Li CY . Enhancing the efficiency of direct reprogramming of human primary fibroblasts into dopaminergic neuron-like cells through p53 suppression. Sci China Life Sci 2014; 57: 867–875.

    CAS  Article  PubMed  Google Scholar 

  56. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010; 7: 618–630.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Liao B, Bao X, Liu L, Feng S, Zovoilis A, Liu W et al. MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. J Biol Chem 2011; 286: 17359–17364.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Lipchina I, Studer L, Betel D . The expanding role of miR-302-367 in pluripotency and reprogramming. Cell Cycle 2012; 11: 1517–1523.

    CAS  Article  PubMed  Google Scholar 

  59. Parchem RJ, Ye J, Judson RL, LaRussa MF, Krishnakumar R, Blelloch A et al. Two miRNA clusters reveal alternative paths in late-stage reprogramming. Cell Stem Cell 2014; 14: 617–631.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Chen T, Hao YJ, Zhang Y, Li MM, Wang M, Han W et al. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015; 16: 289–301.

    CAS  Article  PubMed  Google Scholar 

  61. Galonska C, Ziller MJ, Karnik R, Meissner A . Ground state conditions induce rapid reorganization of core pluripotency factor binding before global epigenetic reprogramming. Cell Stem Cell 2015; 17: 462–470.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011; 476: 228–231.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Shenoy A, Blelloch RH . Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat Rev Mol Cell Biol 2014; 15: 565–576.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H, Li H et al. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 2013; 152: 82–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Nowak JS, Choudhury NR, de Lima Alves F, Rappsilber J, Michlewski G . Lin28a regulates neuronal differentiation and controls miR-9 production. Nat Commun 2014; 5: 3687.

    Article  CAS  PubMed  Google Scholar 

  66. Mertens J, Paquola AC, Ku M, Hatch E, Böhnke L, Ladjevardi S et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 2015; 17: 705–718.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Yang N, Ng YH, Pang ZP, Südhof TC, Wernig M . Induced neuronal cells: how to make and define a neuron. Cell Stem Cell 2011; 9: 517–525.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011; 476: 224–227.

    CAS  Article  PubMed  Google Scholar 

  69. Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA 2011; 108: 10343–10348.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 2011; 9: 413–419.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Jiang H, Xu Z, Zhong P, Ren Y, Liang G, Schilling HA et al. Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun 2015; 6: 10100.

    Article  CAS  PubMed  Google Scholar 

  72. Theka I, Caiazzo M, Dvoretskova E, Leo D, Ungaro F, Curreli S et al. Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. Stem Cells Transl Med 2013; 2: 473–479.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Pollak Dorocic I, Furth D, Xuan Y, Johansson Y, Pozzi L, Silberberg G et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron 2014; 83: 663–678.

    CAS  Article  PubMed  Google Scholar 

  74. Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X, Jappelli R et al. Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 2016; 21: 49–61.

    CAS  Article  PubMed  Google Scholar 

  75. Xu Z, Jiang H, Zhong P, Yan Z, Chen S, Feng J . Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 2016; 21: 62–70.

    CAS  Article  PubMed  Google Scholar 

  76. Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF, Woolf CJ et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 2011; 9: 205–218.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng PY et al. Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 2014; 84: 311–323.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 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  CAS  PubMed  Google Scholar 

  79. Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci USA 2011; 108: 7838–7843.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T et al. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 2012; 10: 473–479.

    CAS  Article  PubMed  Google Scholar 

  81. Yu KR, Shin JH, Kim JJ, Koog MG, Lee JY, Choi SW et al. Rapid and Efficient Direct Conversion of Human Adult Somatic Cells into Neural Stem Cells by HMGA2/let-7b. Cell Rep 2015; 10: S2211–1247 01067–5.

    Article  CAS  PubMed  Google Scholar 

  82. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013; 502: 65–70.

    CAS  Article  PubMed  Google Scholar 

  83. Cacchiarelli D, Trapnell C, Ziller MJ, Soumillon M, Cesana M, Karnik R et al. Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency. Cell 2015; 162: 412–424.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W et al. Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 2015; 17: 204–212.

    CAS  Article  PubMed  Google Scholar 

  85. Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D et al. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 2015; 17: 195–203.

    CAS  Article  PubMed  Google Scholar 

  86. Stevens B . Glia: much more than the neuron's side-kick. Curr Biol 2003; 13: R469–472.

    CAS  Article  PubMed  Google Scholar 

  87. Ogura A, Morizane A, Nakajima Y, Miyamoto S, Takahashi J . gamma-secretase inhibitors prevent overgrowth of transplanted neural progenitors derived from human-induced pluripotent stem cells. Stem Cells Dev 2013; 22: 374–382.

    CAS  Article  PubMed  Google Scholar 

  88. Crawford TQ, Roelink H . The notch response inhibitor DAPT enhances neuronal differentiation in embryonic stem cell-derived embryoid bodies independently of sonic hedgehog signaling. Dev Dyn 2007; 236: 886–892.

    CAS  Article  PubMed  Google Scholar 

  89. Kaiser T, Feng G . Modeling psychiatric disorders for developing effective treatments. Nat Med 2015; 21: 979–988.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 2014; 46: 989–993.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013; 45: 1150–1159.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 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: 703–717.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  95. Farra N, Zhang WB, Pasceri P, Eubanks JH, Salter MW, Ellis J . Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Mol Psychiatry 2012; 17: 1261–1271.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 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: 527–539.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 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: 361–368.

    CAS  Article  PubMed  Google Scholar 

  98. Nishizawa M, Chonabayashi K, Nomura M, Tanaka A, Nakamura M, Inagaki A et al. Epigenetic Variation between Human Induced Pluripotent Stem Cell Lines Is an Indicator of Differentiation Capacity. Cell Stem Cell 2016; 19: 341–354.

    CAS  Article  PubMed  Google Scholar 

  99. Aubert J, Stavridis MP, Tweedie S, O'Reilly M, Vierlinger K, Li M et al. Screening for mammalian neural genes via fluorescence-activated cell sorter purification of neural precursors from Sox1-gfp knock-in mice. Proc Natl Acad Sci USA 2003; 100: 11836–11841.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ . miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34: D140–144.

    CAS  Article  PubMed  Google Scholar 

  101. Miki K, Endo K, Takahashi S, Funakoshi S, Takei I, Katayama S et al. Efficient Detection and Purification of Cell Populations Using Synthetic MicroRNA Switches. Cell Stem Cell 2015; 16: 699–711.

    CAS  Article  PubMed  Google Scholar 

  102. Jiang X, Shen S, Cadwell CR, Berens P, Sinz F, Ecker AS et al. Principles of connectivity among morphologically defined cell types in adult neocortex. Science 2015; 350: aac9462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Frei AP, Bava FA, Zunder ER, Hsieh EW, Chen SY, Nolan GP et al. Highly multiplexed simultaneous detection of RNAs and proteins in single cells. Nat Methods 2016; 13: 269–275.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. Zhang Z, Hong Y, Xiang D, Zhu P, Wu E, Li W et al. MicroRNA-302/367 cluster governs hESC self-renewal by dually regulating cell cycle and apoptosis pathways. Stem Cell Reports 2015; 4: 645–657.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Gao Z, Zhu X, Dou Y . The miR-302/367 cluster: a comprehensive update on its evolution and functions. Open Biol 2015; 5: 150138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kuo CH, Deng JH, Deng Q, Ying SY . A novel role of miR-302/367 in reprogramming. Biochem Biophys Res Commun 2012; 417: 11–16.

    CAS  Article  PubMed  Google Scholar 

  107. Parr CJ, Katayama S, Miki K, Kuang Y, Yoshida Y, Morizane A et al. MicroRNA-302 switch to identify and eliminate undifferentiated human pluripotent stem cells. Sci Rep 2016; 6: 32532.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Endo K, Hayashi K, Saito H . High-resolution Identification and Separation of Living Cell Types by Multiple microRNA-responsive Synthetic mRNAs. Sci Rep 2016; 6: 21991.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 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: 373–379.

    CAS  Article  PubMed  Google Scholar 

  110. Garcez PP, Loiola EC, Madeiro da Costa R, Higa LM, Trindade P, Delvecchio R et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 2016; 352: 816–818.

    CAS  Article  PubMed  Google Scholar 

  111. Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 2016; 534: 267–271.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 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: 288–296.

    CAS  Article  PubMed  Google Scholar 

  113. 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: 681–686.

    CAS  Article  PubMed  Google Scholar 

  114. Aubert J, Dunstan H, Chambers I, Smith A . Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol 2002; 20: 1240–1245.

    CAS  Article  PubMed  Google Scholar 

  115. Parisi S, D'Andrea D, Lago CT, Adamson ED, Persico MG, Minchiotti G . Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. J Cell Biol 2003; 163: 303–314.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 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: 51–56.

    CAS  Article  PubMed  Google Scholar 

  117. Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M et al. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci USA 2013; 110: 20284–20289.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Dehay C, Kennedy H, Kosik KS . The outer subventricular zone and primate-specific cortical complexification. Neuron 2015; 85: 683–694.

    CAS  Article  PubMed  Google Scholar 

  119. Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Bräuninger M et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA 2015; 112: 15672–15677.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Florio M, Huttner WB . Neural progenitors, neurogenesis and the evolution of the neocortex. Development 2014; 141: 2182–2194.

    CAS  Article  PubMed  Google Scholar 

  121. Lancaster MA, Knoblich JA . Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014; 345: 1247125.

    Article  CAS  PubMed  Google Scholar 

  122. Otani T, Marchetto MC, Gage FH, Simons BD, Livesey FJ . 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Cell Stem Cell 2016; 18: 467–480.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Stahl R, Walcher T, De Juan Romero C, Pilz GA, Cappello S, Irmler M et al. Trnp1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate. Cell 2013; 153: 535–549.

    CAS  Article  PubMed  Google Scholar 

  124. Bond J, Roberts E, Springell K, Lizarraga SB, Lizarraga S, Scott S et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 2005; 37: 353–355.

    CAS  Article  PubMed  Google Scholar 

  125. Pagnamenta AT, Murray JE, Yoon G, Sadighi Akha E, Harrison V, Bicknell LS et al. A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss. Am J Med Genet A 2012; 158A: 2577–2582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 2016; 165: 1238–1254.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH . Advancing the understanding of autism disease mechanisms through genetics. Nat Med 2016; 22: 345–361.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. Rubenstein JL . Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol 2010; 23: 118–123.

    Article  PubMed  Google Scholar 

  129. Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L et al. FOXG1-dependent dysregulation of GABA/Glutamate neuron differentiation in autism spectrum disorders. Cell 2015; 162: 375–390.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 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 USA 2012; 109: 12770–12775.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Ariani F, Hayek G, Rondinella D, Artuso R, Mencarelli MA, Spanhol-Rosseto A et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008; 83: 89–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Göke J et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 2016; 19: 248–257.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. Lin L, Göke J, Cukuroglu E, Dranias MR, VanDongen AM, Stanton LW . Molecular features underlying neurodegeneration identified through in vitro modeling of genetically diverse Parkinson's disease patients. Cell Rep 2016; 15: 2411–2426.

    CAS  Article  PubMed  Google Scholar 

  134. Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 2012; 4: 145ra104.

    Article  CAS  PubMed  Google Scholar 

  135. Li HL, Fujimoto N, Sasakawa N, Shirai S, Ohkame T, Sakuma T et al. Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports 2015; 4: 143–154.

    CAS  Article  PubMed  Google Scholar 

  136. Morizane A, Doi D, Kikuchi T, Okita K, Hotta A, Kawasaki T et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Reports 2013; 1: 283–292.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM . Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 2012; 11: 147–152.

    CAS  Article  PubMed  Google Scholar 

  138. Mullokandov G, Baccarini A, Ruzo A, Jayaprakash AD, Tung N, Israelow B et al. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nat Methods 2012; 9: 840–846.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007; 129: 1401–1414.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. Wroblewska L, Kitada T, Endo K, Siciliano V, Stillo B, Saito H et al. Mammalian synthetic circuits with RNA binding proteins for RNA-only delivery. Nat Biotechnol 2015; 33: 839–841.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Asuka Morizane and Peter Karagiannis (CiRA, Kyoto University) for reading and editing the manuscript. We also thank Masaya Todani (CiRA, Kyoto University) for the figures. This work was supported by the CiRA Research Fund for Internationalization.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H Saito.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Parr, C., Yamanaka, S. & Saito, H. An update on stem cell biology and engineering for brain development. Mol Psychiatry 22, 808–819 (2017). https://doi.org/10.1038/mp.2017.66

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.66

Further reading

Search

Quick links