Induced pluripotent stem cell technology: A decade of progress

Nature Reviews Drug Discovery

Volumn 16, Issue 2, 2017, Pages 115-130

  Shi, Yanhong ^a   Inoue, Haruhisa ^b   Wu, Joseph C ^c   Yamanaka, Shinya ^b,d  

^a CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

^b KYOTO UNIVERSITY   (Japan)

^c STANFORD UNIVERSITY   (United States)

^d GLADSTONE INSTITUTE OF CARDIOVASCULAR DISEASE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENALFOCIN; CYTIDINE DEAMINASE; POTASSIUM CHANNEL HERG; RETIGABINE; SURVIVAL MOTOR NEURON PROTEIN; TRANSCRIPTION ACTIVATOR LIKE EFFECTOR NUCLEASE; ZINC FINGER NUCLEASE;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; CARDIOTOXICITY; CELL AGING; CELL DIFFERENTIATION; CELL REPROGRAMMING TECHNIQUE; COCULTURE; CRISPR CAS SYSTEM; DISEASE MODEL; DRUG REPOSITIONING; DRUG SCREENING; EMBRYONIC STEM CELL; GENE EDITING; GOOD MANUFACTURING PRACTICE; HUMAN; INDUCED PLURIPOTENT STEM CELL; LIVER TOXICITY; MACULAR DEGENERATION; MUTAGENESIS; NONHUMAN; PARKINSON DISEASE; PERSONALIZED MEDICINE; REVIEW; SPINAL MUSCULAR ATROPHY; STEM CELL TRANSPLANTATION; TERATOGENICITY; DRUG DEVELOPMENT; DRUG THERAPY; HIGH THROUGHPUT SCREENING; HISTORY; REGENERATIVE MEDICINE; TRENDS;

DRUG DISCOVERY; DRUG THERAPY; HIGH-THROUGHPUT SCREENING ASSAYS; HISTORY, 21ST CENTURY; HUMANS; INDUCED PLURIPOTENT STEM CELLS; REGENERATIVE MEDICINE; STEM CELL TRANSPLANTATION;

EID: 85006285022     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.245     Document Type: Review

References (223)

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.
2. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872 (2007).
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.
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).
5. Scudellari, M. How iPS cells changed the world. Nature 534, 310-312 (2016).
6. Trounson, A. & DeWitt, N. D. Pluripotent stem cells progressing to the clinic. Nat. Rev. Mol. Cell Biol. 17, 194-200 (2016).
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).
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).
9. Ben-David, U., Kopper, O. & Benvenisty, N. Expanding the boundaries of embryonic stem cells. Cell Stem Cell 10, 666-677 (2012).
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).
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).
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).
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).
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.
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).
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).
17. Christian, M. et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186, 757-761 (2010).
18. Hockemeyer, D. et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat. Biotechnol. 29, 731-734 (2011).
19. Sanjana, N. E. et al. A transcription activator-like effector toolbox for genome engineering. Nat. Protoc. 7, 171-192 (2012).
20. Cong, L. et al. Multiplex genome engineering using CRISPR-Cas systems. Science 339, 819-823 (2013).
21. Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10, 973-976 (2013).
22. Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84-87 (2014).
23. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821 (2012).
24. Fu, Y. et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat. Biotechnol. 31, 822-826 (2013).
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).
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).
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).
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).
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).
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).
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).
32. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013).
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).
34. Ran, F. A. et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380-1389 (2013).
35. Slaymaker, I. M. et al. Rationally engineered Cas9 nucleases with improved specificity. Science 351, 84-88 (2016).
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).
37. Paquet, D. et al. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR-Cas9. Nature 533, 125-129 (2016).
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).
39. Ebert, A. D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277-280 (2009).
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.
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.
42. Munsat, T. L. & Davies, K. E. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul. Disord. 2, 423-428 (1992).
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).
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).
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).
46. Liu, G. H. et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491, 603-607 (2012).
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).
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).
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.
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.
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).
52. Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39-44 (2002).
53. Tian, E. et al. Small-molecule-based lineage reprogramming creates functional astrocytes. Cell Rep. 16, 781-792 (2016).
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).
55. Soldner, F. et al. Parkinson-Associated risk variant in distal enhancer of a-synuclein modulates target gene expression. Nature 533, 95-99 (2016).
56. Yagi, T. et al. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum. Mol. Genet. 20, 4530-4539 (2011).
57. Israel, M. A. et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216-220 (2012).
58. Woodruff, G. et al. The presenilin-1 ?E9 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).
59. Mertens, J. et al. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based ?-secretase modulation. Stem Cell Reports 1, 491-498 (2013).
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).
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).
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).
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).
64. Liu, Q. et al. Effect of potent ?-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 71, 1481-1489 (2014).
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).
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).
67. Moore, S. et al. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 11, 689-696 (2015).
68. Liao, M. C. et al. Single-cell detection of secreted Aβ and sAPPa from human IPSC-derived neurons and astrocytes. J. Neurosci. 36, 1730-1746 (2016).
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).
70. Devine, M. J. et al. Parkinson's disease induced pluripotent stem cells with triplication of the a-synuclein locus. Nat. Commun. 2, 440 (2011).
71. Imaizumi, Y. et al. Mitochondrial dysfunction associated with increased oxidative stress and a-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol. Brain 5, 35 (2012).
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).
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).
74. Chung, C. Y. et al. Identification and rescue of a-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983-987 (2013).
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).
76. Ryan, S. D. et al. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1a transcription. Cell 155, 1351-1364 (2013).
77. Hartfield, E. M. et al. Physiological characterisation of human iPS-derived dopaminergic neurons. PLoS ONE 9, e87388 (2014).
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).
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).
80. Dettmer, U. et al. Parkinson-causing a-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).
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).
82. Ren, Y. et al. Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33, 68-78 (2015).
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).
84. Aflaki, E. et al. New glucocerebrosidase chaperone reduces a-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism. J. Neurosci. 36, 7441-7452 (2016).
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.
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).
87. Wen, Z. et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414-418 (2014).
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).
89. Brennand, K. et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol. Psychiatry 20, 361-368 (2014).
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).
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).
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).
93. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615-622 (2007).
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).
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).
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).
97. Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).
98. McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400-404 (2016).
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.
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).
101. Ogawa, M. et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat. Biotechnol. 33, 853-861 (2015).
102. Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, e05098 (2015).
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.
104. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564-568 (2015).
105. Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310-1314 (2014).
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).
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).
108. Mariani, J. et al. FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375-390 (2015).
109. Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267-271 (2016).
110. Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238-1254 (2016).
111. Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816-818 (2016).
112. Gabriel, E. et al. CPAP promotes timely cilium disassembly to maintain neural progenitor pool. EMBO J. 35, 803-819 (2016).
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).
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).
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).
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).
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.
118. Vincent, F. et al. Developing predictive assays: the phenotypic screening "rule of 3". Sci. Transl Med. 7, 293ps15 (2015).
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.
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).
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.
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).
123. Egawa, N. et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl. Med. 4, 145ra104 (2012).
124. Miki, K. et al. Efficient detection and purification of cell populations using synthetic microRNA switches. Cell Stem Cell 16, 699-711 (2015).
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).
126. Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693-709 (2015).
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).
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).
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).
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.
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).
132. Pereira, C. F., Lemischka, I. R. & Moore, K. Reprogramming cell fates: insights from combinatorial approaches. Ann. NY Acad. Sci. 1266, 7-17 (2012).
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).
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).
135. Inoue, H. & Yamanaka, S. The use of induced pluripotent stem cells in drug development. Clin. Pharmacol. Ther. 89, 655-661 (2011).
136. Yamashita, A. et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 513, 507-511 (2014).
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).
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).
139. Avorn, J. The $2.6 billion pill-methodologic and policy considerations. N. Engl. J. Med. 372, 1877-1879 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
148. Takayama, K. et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4a transduction. Mol. Ther. 20, 127-137 (2012).
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).
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.
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).
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).
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).
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).
155. Lund, R. J., Narva, E. & Lahesmaa, R. Genetic and epigenetic stability of human pluripotent stem cells. Nat. Rev. Genet. 13, 732-744 (2012).
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).
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).
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).
159. Cao, F. et al. Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation. Cancer Res. 69, 2709-2713 (2009).
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).
161. Koch, C. A., Geraldes, P. & Platt, J. L. Immunosuppression by embryonic stem cells. Stem Cells 26, 89-98 (2008).
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).
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).
164. Zhao, T., Zhang, Z. N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212-215 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
174. Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920-1923 (2007).
175. Hotta, A. & Yamanaka, S. From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu. Rev. Genet. 49, 47-70 (2015).
176. Deleidi, M. & Yu, C. Genome editing in pluripotent stem cells: research and therapeutic applications. Biochem. Biophys. Res. Commun. 473, 665-674 (2016).
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).
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).
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).
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).
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).
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).
183. Miura, K. et al. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 27, 743-745 (2009).
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).
185. Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 17, 183-193 (2016).
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.
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).
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).
189. Ozone, C. et al. Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat. Commun. 7, 10351 (2016).
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).
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).
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).
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).
194. Goodridge, H. S. Induced pluripotent stem cell-derived myeloid phagocytes: disease modeling and therapeutic applications. Drug Discov. Today 19, 774-780 (2014).
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).
196. Huch, M. & Koo, B. K. Modeling mouse and human development using organoid cultures. Development 142, 3113-3125 (2015).
197. Sasai, Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318-326 (2013).
198. Li, Y., Xu, C. & Ma, T. In vitro organogenesis from pluripotent stem cells. Organogenesis 10, 159-163 (2014).
199. Yin, X. et al. Engineering stem cell organoids. Cell Stem Cell 18, 25-38 (2016).
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).
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.
202. Lord, J., Lu, A. J. & Cruchaga, C. Identification of rare variants in Alzheimer's disease. Front. Genet. 5, 369 (2014).
203. Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1-11 (2014).
204. Yamanaka, S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678-684 (2012).
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).
206. Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797-801 (2009).
207. Okita, K. et al. A more efficient method to generate integration-free human iPS cells. Nat. Methods 8, 409-412 (2011).
208. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945-949 (2008).
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).
210. Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766-770 (2009).
211. Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nat. Methods 7, 197-199 (2010).
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).
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).
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).
215. Miyoshi, N. et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633-638 (2011).
216. Hou, P. et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341, 651-654 (2013).
217. Urnov, F. D. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435, 646-651 (2005).
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).
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).
220. Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2, e00471 (2013).
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).
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).
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).