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  • Review Article
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Induced pluripotent stem cell technology: a decade of progress

Nature Reviews Drug Discovery volume 16, pages 115–130 (2017)Cite this article

Subjects

Key Points

  • Human induced pluripotent stem cell (iPSC) technology has evolved rapidly since its inception in 2007.

  • Human iPSC technology has been widely used for disease modelling; for example, for neurodegenerative and psychiatric disorders.

  • Human iPSC technology has yielded several drug candidates that are currently in clinical trials.

  • The first clinical trial using human iPSC-derived products has been initiated for age-related macular degeneration.

  • The combination with gene editing and 3D organoid technologies makes the iPSC platform more powerful.

  • The continued development of iPSC technology and its integration with other technologies has the potential to make substantial contributions to disease modelling, drug discovery and regenerative medicine.

Abstract

Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field.

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Figure 1: A schematic for human iPSC-based disease modelling.
Figure 2: A schematic for human iPSC-based cell therapy.

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References

  1. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). The first report to describe iPSC technology.

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007). References 2 and 3 are the first studies to demonstrate human iPSC derivation from somatic cells.

    Article  CAS  PubMed  Google Scholar 

  4. Kimbrel, E. A. & Lanza, R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat. Rev. Drug Discov. 14, 681–692 (2015).

    CAS  PubMed  Google Scholar 

  5. Scudellari, M. How iPS cells changed the world. Nature 534, 310–312 (2016).

    PubMed  Google Scholar 

  6. Trounson, A. & DeWitt, N. D. Pluripotent stem cells progressing to the clinic. Nat. Rev. Mol. Cell Biol. 17, 194–200 (2016).

    CAS  PubMed  Google Scholar 

  7. Onos, K. D., Sukoff Rizzo, S. J., Howell, G. R. & Sasner, M. Toward more predictive genetic mouse models of Alzheimer's disease. Brain Res. Bull. 122, 1–11 (2016).

    CAS  PubMed  Google Scholar 

  8. Puzzo, D., Gulisano, W., Palmeri, A. & Arancio, O. Rodent models for Alzheimer's disease drug discovery. Expert Opin. Drug Discov. 10, 703–711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ben-David, U., Kopper, O. & Benvenisty, N. Expanding the boundaries of embryonic stem cells. Cell Stem Cell 10, 666–677 (2012).

    CAS  PubMed  Google Scholar 

  10. Kim, K. et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat. Biotechnol. 29, 1117–1119 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat. Cell Biol. 13, 541–549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bar-Nur, O., Russ, H. A., Efrat, S. & Benvenisty, N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9, 17–23 (2011).

    CAS  PubMed  Google Scholar 

  13. Avior, Y., Sagi, I. & Benvenisty, N. Pluripotent stem cells in disease modelling and drug discovery. Nat. Rev. Mol. Cell Biol. 17, 170–182 (2016).

    CAS  PubMed  Google Scholar 

  14. Hockemeyer, D. & Jaenisch, R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573–586 (2016). A comprehensive review of iPSCs and genome editing.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hockemeyer, D. et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat. Biotechnol. 27, 851–857 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zou, J. et al. Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell 5, 97–110 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Christian, M. et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186, 757–761 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hockemeyer, D. et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat. Biotechnol. 29, 731–734 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sanjana, N. E. et al. A transcription activator-like effector toolbox for genome engineering. Nat. Protoc. 7, 171–192 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cong, L. et al. Multiplex genome engineering using CRISPR–Cas systems. Science 339, 819–823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR–Cas9-based transcription factors. Nat. Methods 10, 973–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shalem, O. et al. Genome-scale CRISPR–Cas9 knockout screening in human cells. Science 343, 84–87 (2014).

    CAS  PubMed  Google Scholar 

  23. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Fu, Y. et al. High-frequency off-target mutagenesis induced by CRISPR–Cas nucleases in human cells. Nat. Biotechnol. 31, 822–826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Smith, C. et al. Whole-genome sequencing analysis reveals high specificity of CRISPR–Cas9 and TALEN-based genome editing in human iPSCs. Cell Stem Cell 15, 12–13 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Veres, A. et al. Low incidence of off-target mutations in individual CRISPR–Cas9 and TALEN targeted human stem cell clones detected by whole-genome sequencing. Cell Stem Cell 15, 27–30 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, C. et al. Novel HDAd/EBV reprogramming vector and highly efficient Ad/CRISPR–Cas sickle cell disease gene correction. Sci. Rep. 6, 30422 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chang, C. W. et al. Modeling human severe combined immunodeficiency and correction by CRISPR–Cas9-enhanced gene targeting. Cell Rep. 12, 1668–1677 (2015).

    CAS  PubMed  Google Scholar 

  29. Park, C. Y. et al. Functional correction of large factor VIII gene chromosomal inversions in hemophilia A patient-derived iPSCs using CRISPR–Cas9. Cell Stem Cell 17, 213–220 (2015).

    CAS  PubMed  Google Scholar 

  30. Firth, A. L. et al. Functional gene correction for cystic fibrosis in lung epithelial cells generated from patient iPSCs. Cell Rep. 12, 1385–1390 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bae, S., Park, J. & Kim, J. S. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics 30, 1473–1475 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dominguez, A. A., Lim, W. A. & Qi, L. S. Beyond editing: repurposing CRISPR–Cas9 for precision genome regulation and interrogation. Nat. Rev. Mol. Cell Biol. 17, 5–15 (2016).

    CAS  PubMed  Google Scholar 

  34. Ran, F. A. et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380–1389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Slaymaker, I. M. et al. Rationally engineered Cas9 nucleases with improved specificity. Science 351, 84–88 (2016).

    CAS  PubMed  Google Scholar 

  36. Chen, B. et al. Dynamic imaging of genomic loci in living human cells by an optimized CRISPR–Cas system. Cell 155, 1479–1491 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Paquet, D. et al. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR–Cas9. Nature 533, 125–129 (2016).

    CAS  PubMed  Google Scholar 

  38. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ebert, A. D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009).

    CAS  PubMed  Google Scholar 

  40. Lee, G. et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402–406 (2009). References 39 and 40 are the first studies to demonstrate disease-associated phenotypes in patient-derived iPSC-based disease modelling.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Studer, L., Vera, E. & Cornacchia, D. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell 16, 591–600 (2015). An important review article discussing how cellular age is erased during iPSC derivation and how the iPSC platform may be used to programme cellular ageing along with cellular fate.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Munsat, T. L. & Davies, K. E. International SMA consortium meeting. (26–28 June 1992, Bonn, Germany). Neuromuscul. Disord. 2, 423–428 (1992).

    CAS  PubMed  Google Scholar 

  43. Nguyen, H. N. et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cooper, O. et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Sci. Transl Med. 4, 141ra90 (2012).

    PubMed  PubMed Central  Google Scholar 

  45. Miller, J. D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, G. H. et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491, 603–607 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pearson, B. L. et al. Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration. Nat. Commun. 7, 11173 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ho, R. et al. ALS disrupts spinal motor neuron maturation and aging pathways within gene co-expression networks. Nat. Neurosci. 19, 1256–1267 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mertens, J., Marchetto, M. C., Bardy, C. & Gage, F. H. Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nat. Rev. Neurosci. 17, 424–437 (2016). A comprehensive review of cell reprogramming, differentiation and conversion technologies in neuroscience.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mertens, J. et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17, 705–718 (2015). Demonstrates for the first time that directly reprogrammed human neurons preserve cellular age.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bardy, C. et al. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc. Natl Acad. Sci. USA 112, E2725–E2734 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002).

    CAS  PubMed  Google Scholar 

  53. Tian, E. et al. Small-molecule-based lineage reprogramming creates functional astrocytes. Cell Rep. 16, 781–792 (2016).

    CAS  PubMed  Google Scholar 

  54. Kondo, T. et al. Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 12, 487–496 (2013).

    CAS  PubMed  Google Scholar 

  55. Soldner, F. et al. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533, 95–99 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Yagi, T. et al. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum. Mol. Genet. 20, 4530–4539 (2011).

    CAS  PubMed  Google Scholar 

  57. Israel, M. A. et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Woodruff, G. et al. The presenilin-1 ΔE9 mutation results in reduced gamma-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 5, 974–985 (2013).

    CAS  PubMed  Google Scholar 

  59. Mertens, J. et al. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Reports 1, 491–498 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee, J. K. et al. Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease. J. Exp. Med. 211, 1551–1570 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Duan, L. et al. Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death. Mol. Neurodegener. 9, 3 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. Muratore, C. R. et al. The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum. Mol. Genet. 23, 3523–3536 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Mahairaki, V. et al. Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. Stem Cells Dev. 23, 2996–3010 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu, Q. et al. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 71, 1481–1489 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Young, J. E. et al. Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16, 373–385 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hossini, A. M. et al. Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks. BMC Genomics 16, 84 (2015).

    PubMed  PubMed Central  Google Scholar 

  67. Moore, S. et al. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 11, 689–696 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Liao, M. C. et al. Single-cell detection of secreted Aβ and sAPPα from human IPSC-derived neurons and astrocytes. J. Neurosci. 36, 1730–1746 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Seibler, P. et al. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J. Neurosci. 31, 5970–5976 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Devine, M. J. et al. Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat. Commun. 2, 440 (2011).

    PubMed  Google Scholar 

  71. Imaizumi, Y. et al. Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol. Brain 5, 35 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  73. Sanchez-Danes, A. et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380–395 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chung, C. Y. et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Reinhardt, P. et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12, 354–367 (2013).

    CAS  PubMed  Google Scholar 

  76. Ryan, S. D. et al. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155, 1351–1364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hartfield, E. M. et al. Physiological characterisation of human iPS-derived dopaminergic neurons. PLoS ONE 9, e87388 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Schondorf, D. C. et al. iPSC-derived neurons from GBA1-associated Parkinson's disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 5, 4028 (2014).

    PubMed  Google Scholar 

  79. Woodard, C. M. et al. iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. Cell Rep. 9, 1173–1182 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Dettmer, U. et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).

    PubMed  Google Scholar 

  81. Fernandez-Santiago, R. et al. Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients. EMBO Mol. Med. 7, 1529–1546 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ren, Y. et al. Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33, 68–78 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Shaltouki, A. et al. Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines. Stem Cell Reports 4, 847–859 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Aflaki, E. et al. New glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism. J. Neurosci. 36, 7441–7452 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011). The first study to use a human iPSC model for a psychiatric disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Lin, M. 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 6, e23356 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wen, Z. et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414–418 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Murai, K. et al. The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat. Commun. 7, 10965 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Brennand, K. et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol. Psychiatry 20, 361–368 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Topol, A. et al. Dysregulation of miRNA-9 in a subset of schizophrenia patient-derived neural progenitor cells. Cell Rep. 15, 1024–1036 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yoon, K. J. et al. 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 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Han, J. et al. Functional implications of miR-19 in the migration of newborn neurons in the adult brain. Neuron 91, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  93. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T. & Eggan, K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat. Neurosci. 10, 608–614 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Marchetto, M. C. et al. Non-cell-autonomous effect of human SOD1G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649–657 (2008).

    CAS  PubMed  Google Scholar 

  96. Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat. Biotechnol. 29, 824–828 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).

    PubMed  Google Scholar 

  98. McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400–404 (2016).

    Google Scholar 

  99. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013). The first report to describe the generation and transplantation of human iPSC-derived organoids.

    CAS  PubMed  Google Scholar 

  100. Sampaziotis, F. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat. Biotechnol. 33, 845–852 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ogawa, M. et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat. Biotechnol. 33, 853–861 (2015).

    CAS  PubMed  Google Scholar 

  102. Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, e05098 (2015).

    PubMed Central  Google Scholar 

  103. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011). A pioneering report of human iPSC-derived organoids.

    PubMed  Google Scholar 

  104. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

    CAS  PubMed  Google Scholar 

  105. Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Tucker, B. A. et al. Duplication of TBK1 stimulates autophagy in iPSC-derived retinal cells from a patient with normal tension glaucoma. J. Stem Cell Res. Ther. 3, 161 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. Camp, J. G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl Acad. Sci. USA 112, 15672–15677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375–390 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).

    CAS  PubMed  Google Scholar 

  112. Gabriel, E. et al. CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35, 803–819 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Otani, T., Marchetto, M. C., Gage, F. H., Simons, B. D. & Livesey, F. J. 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size. Cell Stem Cell 18, 467–480 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Pasca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671–678 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Tzatzalos, E., Abilez, O. J., Shukla, P. & Wu, J. C. Engineered heart tissues and induced pluripotent stem cells: macro- and microstructures for disease modeling, drug screening, and translational studies. Adv. Drug Deliv. Rev. 96, 234–244 (2016).

    CAS  PubMed  Google Scholar 

  116. Fatehullah, A., Tan, S. H. & Barker, N. Organoids as an in vitro model of human development and disease. Nat. Cell Biol. 18, 246–254 (2016).

    PubMed  Google Scholar 

  117. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). The first report to describe human iPSC-derived brain organoids and disease modelling using human iPSC-originated organoids.

    CAS  PubMed  Google Scholar 

  118. Vincent, F. et al. Developing predictive assays: the phenotypic screening “rule of 3”. Sci. Transl Med. 7, 293ps15 (2015).

    PubMed  Google Scholar 

  119. Inoue, H., Nagata, N., Kurokawa, H. & Yamanaka, S. iPS cells: a game changer for future medicine. EMBO J. 33, 409–417 (2014). A comprehensive review of patient stratification using patient iPSCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Matsa, E. et al. Transcriptome profiling of patient-specific human iPSC-cardiomyocytes predicts individual drug safety and efficacy responses in vitro. Cell Stem Cell 19, 311–325 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lee, G. et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat. Biotechnol. 30, 1244–1248 (2012). The first study to perform large-scale drug screening using a human iPSC-based disease model.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Doi, D. et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Reports 2, 337–350 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Egawa, N. et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl. Med. 4, 145ra104 (2012).

    PubMed  Google Scholar 

  124. Miki, K. et al. Efficient detection and purification of cell populations using synthetic microRNA switches. Cell Stem Cell 16, 699–711 (2015).

    CAS  PubMed  Google Scholar 

  125. Burkhardt, M. F. et al. A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells. Mol. Cell. Neurosci. 56, 355–364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015).

    CAS  PubMed  Google Scholar 

  127. Naryshkin, N. A. et al. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014).

    CAS  PubMed  Google Scholar 

  128. Xu, X. et al. Prevention of β-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of cyclin-dependent kinases and associated cell cycle events. Stem Cell Res. 10, 213–227 (2013).

    CAS  PubMed  Google Scholar 

  129. Hoing, S. et al. Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay. Cell Stem Cell 11, 620–632 (2012).

    PubMed  Google Scholar 

  130. Mullard, A. Stem-cell discovery platforms yield first clinical candidates. Nat. Rev. Drug Discov. 14, 589–591 (2015). Discusses the identification of clinical candidates using stem cell-based discovery platforms.

    CAS  PubMed  Google Scholar 

  131. Wang, H., Li, X., Gao, S., Sun, X. & Fang, H. Transdifferentiation via transcription factors or microRNAs: current status and perspective. Differentiation 90, 69–76 (2015).

    CAS  PubMed  Google Scholar 

  132. Pereira, C. F., Lemischka, I. R. & Moore, K. Reprogramming cell fates: insights from combinatorial approaches. Ann. NY Acad. Sci. 1266, 7–17 (2012).

    CAS  PubMed  Google Scholar 

  133. Tanaka, A. et al. Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi myopathy in vitro. PLoS ONE 8, e61540 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Shoji, E. et al. Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells. Sci. Rep. 5, 12831 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Inoue, H. & Yamanaka, S. The use of induced pluripotent stem cells in drug development. Clin. Pharmacol. Ther. 89, 655–661 (2011).

    CAS  PubMed  Google Scholar 

  136. Yamashita, A. et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 513, 507–511 (2014).

    CAS  PubMed  Google Scholar 

  137. McNeish, J., Gardner, J. P., Wainger, B. J., Woolf, C. J. & Eggan, K. From dish to bedside: lessons learned while translating findings from a stem cell model of disease to a clinical trial. Cell Stem Cell 17, 8–10 (2015).

    CAS  PubMed  Google Scholar 

  138. Devlin, A. C. et al. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat. Commun. 6, 5999 (2015).

    CAS  PubMed  Google Scholar 

  139. Avorn, J. The $2.6 billion pill — methodologic and policy considerations. N. Engl. J. Med. 372, 1877–1879 (2015).

    CAS  PubMed  Google Scholar 

  140. DiMasi, J. A., Grabowski, H. G. & Hansen, R. W. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 (2016).

    PubMed  Google Scholar 

  141. Wilke, R. A. et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat. Rev. Drug Discov. 6, 904–916 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Lu, H. R. et al. Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines. Br. J. Pharmacol. 154, 1427–1438 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Doherty, K. R. et al. Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol. Appl. Pharmacol. 272, 245–255 (2013).

    CAS  PubMed  Google Scholar 

  144. Gintant, G., Sager, P. T. & Stockbridge, N. Evolution of strategies to improve preclinical cardiac safety testing. Nat. Rev. Drug Discov. 15, 457–471 (2016).

    CAS  PubMed  Google Scholar 

  145. Harris, K. et al. Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol. Sci. 134, 412–426 (2013).

    CAS  PubMed  Google Scholar 

  146. Qu, Y. & Vargas, H. M. Proarrhythmia risk assessment in human induced pluripotent stem cell-derived cardiomyocytes using the Maestro MEA platform. Toxicol. Sci. 147, 286–295 (2015).

    CAS  PubMed  Google Scholar 

  147. Yamada, T. et al. In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells 20, 146–154 (2002).

    PubMed  Google Scholar 

  148. Takayama, K. et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction. Mol. Ther. 20, 127–137 (2012).

    CAS  PubMed  Google Scholar 

  149. Schwartz, M. P. et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc. Natl Acad. Sci. USA 112, 12516–12521 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998). A pioneering report of human ESC derivation.

    CAS  PubMed  Google Scholar 

  151. Sayed, N., Liu, C. & Wu, J. C. Translation of human-induced pluripotent stem cells: from clinical trial in a dish to precision medicine. J. Am. Coll. Cardiol. 67, 2161–2176 (2016).

    PubMed  PubMed Central  Google Scholar 

  152. Menasche, P. et al. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur. Heart J. 36, 2011–2017 (2015).

    PubMed  Google Scholar 

  153. Neofytou, E., O'Brien, C. G., Couture, L. A. & Wu, J. C. Hurdles to clinical translation of human induced pluripotent stem cells. J. Clin. Invest. 125, 2551–2557 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. Lee, A. S., Tang, C., Rao, M. S., Weissman, I. L. & Wu, J. C. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat. Med. 19, 998–1004 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Lund, R. J., Narva, E. & Lahesmaa, R. Genetic and epigenetic stability of human pluripotent stem cells. Nat. Rev. Genet. 13, 732–744 (2012).

    CAS  PubMed  Google Scholar 

  156. Lee, M. O. et al. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc. Natl Acad. Sci. USA 110, E3281–E3290 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ben-David, U. et al. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell 12, 167–179 (2013).

    CAS  PubMed  Google Scholar 

  158. Nguyen, P. K., Neofytou, E., Rhee, J.-W. & Wu, J. C. Potential strategies for addressing the major clinical hurdles facing stem cell regenerative therapy. JAMA Cardiol. 1, 953–962 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. Cao, F. et al. Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation. Cancer Res. 69, 2709–2713 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Riegler, J. et al. Comparison of magnetic resonance imaging and serum biomarkers for detection of human pluripotent stem cell-derived teratomas. Stem Cell Reports 6, 176–187 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Koch, C. A., Geraldes, P. & Platt, J. L. Immunosuppression by embryonic stem cells. Stem Cells 26, 89–98 (2008).

    CAS  PubMed  Google Scholar 

  162. Drukker, M. et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 9864–9869 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Pearl, J. I., Kean, L. S., Davis, M. M. & Wu, J. C. Pluripotent stem cells: immune to the immune system? Sci. Transl. Med. 4, 164ps125 (2012).

    Google Scholar 

  164. Zhao, T., Zhang, Z. N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).

    CAS  PubMed  Google Scholar 

  165. de Almeida, P. E. et al. Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance. Nat. Commun. 5, 3903 (2014).

    CAS  PubMed  Google Scholar 

  166. Zhao, T. et al. Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17, 353–359 (2015).

    CAS  PubMed  Google Scholar 

  167. Huang, K. et al. Neural progenitor cells from human induced pluripotent stem cells generated less autogenous immune response. Sci. China Life Sci. 57, 162–170 (2014).

    CAS  PubMed  Google Scholar 

  168. Cell Stem Cell Editorial Team. 10 questions: clinical outlook for iPSCs. Cell Stem Cell 18, 170–173 (2016).

  169. Bravery, C. A. Do human leukocyte antigen-typed cellular therapeutics based on induced pluripotent stem cells make commercial sense? Stem Cells Dev. 24, 1–10 (2015).

    PubMed  Google Scholar 

  170. Jacquet, L. et al. Strategy for the creation of clinical grade hESC line banks that HLA-match a target population. EMBO Mol. Med. 5, 10–17 (2013).

    CAS  PubMed  Google Scholar 

  171. Pearl, J. I. et al. Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells. Cell Stem Cell 8, 309–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Swijnenburg, R. J. et al. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc. Natl Acad. Sci. USA 105, 12991–12996 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Meissner, T., Strominger, J. & Cowan, C. The universal donor stem cells: removing the immune barrier to transplantation using CRISPR–Cas9. J. Immunol. 194 (1 Suppl.), 140.128 (2015).

    Google Scholar 

  174. Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2007).

    CAS  PubMed  Google Scholar 

  175. Hotta, A. & Yamanaka, S. From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu. Rev. Genet. 49, 47–70 (2015).

    CAS  PubMed  Google Scholar 

  176. Deleidi, M. & Yu, C. Genome editing in pluripotent stem cells: research and therapeutic applications. Biochem. Biophys. Res. Commun. 473, 665–674 (2016).

    CAS  PubMed  Google Scholar 

  177. Seah, Y. F., El Farran, C. A., Warrier, T., Xu, J. & Loh, Y. H. Induced pluripotency and gene editing in disease modelling: perspectives and challenges. Int. J. Mol. Sci. 16, 28614–28634 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Orqueda, A. J., Gimenez, C. A. & Pereyra-Bonnet, F. iPSCs: a minireview from bench to bed, including organoids and the CRISPR system. Stem Cells Int. 2016, 5934782 (2016).

    PubMed  PubMed Central  Google Scholar 

  179. Koike-Yusa, H., Li, Y., Tan, E. P., del Castillo Velasco-Herrera, M. & Yusa, K. Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library. Nat. Biotechnol. 32, 267–273 (2014).

    CAS  PubMed  Google Scholar 

  180. Mandegar, M. A. et al. CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs. Cell Stem Cell 18, 541–553 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Narsinh, K. H. et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J. Clin. Invest. 121, 1217–1221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Hough, S. R. et al. Single-cell gene expression profiles define self-renewing, pluripotent, and lineage primed states of human pluripotent stem cells. Stem Cell Reports 2, 881–895 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Miura, K. et al. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 27, 743–745 (2009).

    CAS  PubMed  Google Scholar 

  184. Koyanagi-Aoi, M. et al. Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc. Natl Acad. Sci. USA 110, 20569–20574 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 17, 183–193 (2016).

    CAS  PubMed  Google Scholar 

  186. Sasai, Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. Cell Stem Cell 12, 520–530 (2013). A comprehensive review of 3D organoid technology.

    CAS  PubMed  Google Scholar 

  187. Kadoshima, T. 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 110, 20284–20289 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).

    CAS  PubMed  Google Scholar 

  189. Ozone, C. et al. Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat. Commun. 7, 10351 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep. 10, 537–550 (2015).

    CAS  PubMed  Google Scholar 

  191. Sakaguchi, H. et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat. Commun. 6, 8896 (2015).

    CAS  PubMed  Google Scholar 

  192. Dedhia, P. H., Bertaux-Skeirik, N., Zavros, Y. & Spence, J. R. Organoid models of human gastrointestinal development and disease. Gastroenterology 150, 1098–1112 (2016).

    PubMed  Google Scholar 

  193. Aday, S., Cecchelli, R., Hallier-Vanuxeem, D., Dehouck, M. P. & Ferreira, L. Stem cell-based human blood–brain barrier models for drug discovery and delivery. Trends Biotechnol. 34, 382–393 (2016).

    CAS  PubMed  Google Scholar 

  194. Goodridge, H. S. Induced pluripotent stem cell-derived myeloid phagocytes: disease modeling and therapeutic applications. Drug Discov. Today 19, 774–780 (2014).

    CAS  PubMed  Google Scholar 

  195. Smith, M. J. et al. In vitro T-cell generation from adult, embryonic, and induced pluripotent stem cells: many roads to one destination. Stem Cells 33, 3174–3180 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Huch, M. & Koo, B. K. Modeling mouse and human development using organoid cultures. Development 142, 3113–3125 (2015).

    CAS  PubMed  Google Scholar 

  197. Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318–326 (2013).

    CAS  PubMed  Google Scholar 

  198. Li, Y., Xu, C. & Ma, T. In vitro organogenesis from pluripotent stem cells. Organogenesis 10, 159–163 (2014).

    PubMed  PubMed Central  Google Scholar 

  199. Yin, X. et al. Engineering stem cell organoids. Cell Stem Cell 18, 25–38 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Inoue, Y., Shineha, R. & Yashiro, Y. Current public support for human-animal chimera research in Japan is limited, despite high levels of scientific approval. Cell Stem Cell 19, 152–153 (2016).

    CAS  PubMed  Google Scholar 

  201. Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015). Describes a proof-of-concept study showing the potential of iPSCs for investigating individualized drug responsiveness.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Lord, J., Lu, A. J. & Cruchaga, C. Identification of rare variants in Alzheimer's disease. Front. Genet. 5, 369 (2014).

    PubMed  PubMed Central  Google Scholar 

  203. Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1–11 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Yamanaka, S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678–684 (2012).

    CAS  PubMed  Google Scholar 

  205. Hawley, R. G. Does retroviral insertional mutagenesis play a role in the generation of induced pluripotent stem cells? Mol. Ther. 16, 1354–1355 (2008).

    CAS  PubMed  Google Scholar 

  206. Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  208. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 85, 348–362 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nat. Methods 7, 197–199 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Lin, S. L. et al. miR-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 14, 2115–2124 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Miyoshi, N. et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633–638 (2011).

    CAS  PubMed  Google Scholar 

  216. Hou, P. et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341, 651–654 (2013).

    CAS  PubMed  Google Scholar 

  217. Urnov, F. D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435, 646–651 (2005).

    CAS  PubMed  Google Scholar 

  218. Lombardo, A. et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat. Biotechnol. 25, 1298–1306 (2007).

    CAS  PubMed  Google Scholar 

  219. Cho, S. W., Kim, S., Kim, J. M. & Kim, J. S. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31, 230–232 (2013).

    CAS  PubMed  Google Scholar 

  220. Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2, e00471 (2013).

    PubMed  PubMed Central  Google Scholar 

  221. Kaufmann, M. et al. High-throughput screening using iPSC-derived neuronal progenitors to identify compounds counteracting epigenetic gene silencing in Fragile X syndrome. J. Biomol. Screen. 20, 1101–1111 (2015).

    CAS  PubMed  Google Scholar 

  222. Kumari, D. et al. High-throughput screening to identify compounds that increase Fragile X mental retardation protein expression in neural stem cells differentiated from Fragile X syndrome patient-derived induced pluripotent stem cells. Stem Cells Transl. Med. 4, 800–808 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Li, M. et al. Establishment of reporter lines for detecting Fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells http://dx.doi.org/10.1002/stem.2463 (2016).

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Acknowledgements

The authors thank the following individuals: J. Chao, L. Li, Q. Qu and E. Tian for their help in preparing the figures; P. Karagiannis and C. Gandhi for critically reading and editing the manuscript; and R. Carrasco, L. Zaragoza, A. M. Chrisney, M. Kong, Y. Miyake, N. Endo, R. Ueno and R. Okuyama for their administrative support. The work was partially funded by the following agencies and grants: the Herbert Horvitz Fellowship (to Y.S.); the Sidell Kagan Foundation (to Y.S.); the California Institute for Regenerative Medicine grants RB4-06277 (to Y.S.), TRAN1-08525 (to Y.S.), RT3-07798 (to J.C.W.) and DR2A-05394 (to J.C.W.); US National Institutes of Health grants R01 HL130020 (J.C.W.) and R01 HL128170 (J.C.W.); the iPS Cell Research Fund (to S.Y.); the Center for iPSC production, the Program for Intractable Diseases Research utilizing Disease-specific iPS cells, Research Center Network for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) (to S.Y.); the grant for Core Center for iPS cell Research of Research Center Network for Realization of Regenerative Medicine from AMED (to S.Y., H.I.); the Program for Intractable Diseases Research utilizing disease-specific iPS cells from AMED (to H.I.); Research Project for Practical Applications of Regenerative Medicine from AMED (to H.I); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to H.I.); and the Daiichi Sankyo Foundation of Life Science (to H.I.).

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Authors and Affiliations

  1. Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, 91010, California, USA

    Yanhong Shi

  2. Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606–8507, Japan

    Haruhisa Inoue & Shinya Yamanaka

  3. Stanford Cardiovascular Institute, 265 Campus Drive, Room G1120B, Stanford, 94305–5454, California, USA

    Joseph C. Wu

  4. Gladstone Institute of Cardiovascular Disease, San Francisco, 94158, California, USA

    Shinya Yamanaka

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Corresponding authors

Correspondence to Yanhong Shi or Haruhisa Inoue.

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J.C.W. is a co-founder of Stem Cell Theranostics. S.Y. is a non-salaried scientific adviser of iPS Academia Japan. The other authors declare no competing interests.

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Glossary

Embryonic stem cells

(ESCs). Pluripotent stem cells that are derived from the inner cell mass of human embryos.

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells that are reprogrammed from somatic cells by introducing pluripotency factors.

Regenerative medicine

A therapeutic approach in which damaged tissues or organs are replaced by stimulating self-repair or using in vitro-cultured tissues or organs derived from cells, presumably stem cells, of a patient or a donor.

Gene editing

Genetic engineering in which DNA is modified by engineered nucleases. A relevant example is to make isogenic induced pluripotent stem cell lines using gene editing.

CRIPSR–Cas9 technology

A highly popular gene editing tool based on a bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) nuclease from Streptococcus pyogenes. This technology has gained wide usage in gene editing because of its simplicity in design and ease of use.

Precision medicine

A model that aims to offer medical treatment tailored to individual patients.

Whole genome sequencing

(WGS). A high-throughput sequencing technology that uncovers the entire DNA sequence of a genome.

Exome sequencing

A technology that determines the sequence of all expressed genes in a genome. It is also called whole exome sequencing (WES).

Targeted deep sequencing

An approach that determines the sequence at regions of interest using next-generation sequencing technology.

Direct conversion

A technology that enables one type of somatic cell to be reprogrammed into another type of somatic cell.

Organoids

In vitro cultured 3D organ buds that resemble the cellular organization and structure of human organs, but are more primitive and at a smaller scale than endogenous organs.

Good manufacturing practice

A system that guarantees products are manufactured by following specific guidelines recommended by regulatory agencies, such as the US Food and Drug Administration. Such compliance is mandatory for all pharmaceutical manufacturing.

Autologous

Of the same individual.

Allogeneic

Of genetically different individuals from the same species.

MicroRNA switch

A biotechnology that turns a gene on or off depending on the microRNA (or microRNAs) inside the cell.

Disease repositioning

Redefinition of a disease based on disease induced pluripotent stem cell-based phenotypes to identify common and new therapeutic approaches across diseases.

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Shi, Y., Inoue, H., Wu, J. et al. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16, 115–130 (2017). https://doi.org/10.1038/nrd.2016.245

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