Induced pluripotent stem cells (iPSCs) that are derived from patients and differentiated in vitro can provide disease-relevant cell types for drug screening.
Directed differentiation of iPSCs has yielded many disease-relevant cells — chiefly neurons, hepatocytes, blood cells and cardiomyocytes — but often the cells reflect embryonic stages of development, and may not faithfully reflect disease phenotypes of adult tissues.
Methods for deriving iPSCs are evolving, and much remains to be learned about the genetic and epigenetic stability of iPSCs and their relationships to embryonic stem cells, and how this affects the fidelity of drug screening.
Notwithstanding a few exceptions, disease modelling so far has focused on Mendelian disorders of high clinical penetrance and with a recognized cellular pathophysiology, such as spinal muscular atrophy, familial dysautonomia, Rett syndrome, Hutchinson–Gilford progeria syndrome and long QT syndrome. Whether more complex, sporadically occurring disease entities can be modelled with iPSCs remains uncertain.
Cell-based assays enable the discovery of novel pathways and the identification of compounds with favourable cell permeability and toxicity profiles, but such assays are less amenable to defining the structure–activity relationships that are important for optimizing drug properties.
iPSCs offer important advantages for drug toxicity screening against relevant human cells and tissues, and may facilitate the development of 'in vitro clinical trials' to test the efficacy of drugs or gene correction vectors against various distinct patient genotypes.
The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSCs can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling a 'disease in a dish' and for testing compounds against human disease phenotypes in vitro. We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets and enhance the probability of clinical success of new drugs.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nature Rev. Drug Discov. 5, 835–844 (2006).
Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000).
Jacoby, E., Bouhelal, R., Gerspacher, M. & Seuwen, K. The 7 TM G-protein-coupled receptor target family. ChemMedChem 1, 761–782 (2006).
Pouton, C. W. & Haynes, J. M. Embryonic stem cells as a source of models for drug discovery. Nature Rev. Drug Discov. 6, 605–616 (2007).
Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).
Davila, J. C. et al. Use and application of stem cells in toxicology. Toxicol. Sci. 79, 214–223 (2004).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This was the first demonstration that mouse somatic cells can be reprogrammed into PSCs following the introduction of a defined set of transcription factors.
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Lowry, W. E. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl Acad. Sci. USA 105, 2883–2888 (2008).
Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008). This paper describes human iPSCs created from several diseases, including complex adult-onset diseases.
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). References 8, 9 and 11 were the first reports of the generation of iPSCs from human somatic cells by defined transcription factors.
Urbach, A., Bar-Nur, O., Daley, G. Q. & Benvenisty, N. Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407–411 (2010).
Lee, G. et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402–406 (2009). This work demonstrates that reprogrammed cells from patients with monogenic developmental diseases can recapitulate a disease-relevant phenotype, and that these disease phenotypes can be modified by drugs.
Carvajal-Vergara, X. et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465, 808–812 (2010).
Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).
Zhang, J. et al. A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011). This paper demonstrates that several disease-relevant cell types differentiated from reprogrammed cells (taken from patients) show disease phentoypes.
Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010).
Rashid, S. T. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127–3136 (2010).
Ebert, A. D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009). This work also demonstrates that reprogrammed cells from patients with monogenic developmental diseases can recapitulate a disease-relevant phenotype, and that these disease phenotypes can be modified by drugs.
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).
McNeish, J. et al. High-throughput screening in embryonic stem cell-derived neurons identifies potentiators of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-type glutamate receptors. J. Biol. Chem. 285, 17209–17217 (2010). This was the first demonstration that cells differentiated from iPSCs can be used in high-throughput screens to discover new chemical entities.
Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nature Genet. 37, 1099–1103 (2005).
Baker, D. E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nature Biotech. 25, 207–215 (2007).
Narva, E. et al. High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotech. 28, 371–377 (2010). This paper shows that chromosomal abnormalities accumulate during the passaging of human embryonic stem cells.
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).
Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).
Blelloch, R., Venere, M., Yen, J. & Ramalho-Santos, M. Generation of induced pluripotent stem cells in the absence of drug selection. Cell Stem Cell 1, 245–247 (2007).
Meissner, A., Wernig, M. & Jaenisch, R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nature Biotech. 25, 1177–1181 (2007).
Wernig, M., Meissner, A., Cassady, J. P. & Jaenisch, R. c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10–12 (2008).
Boland, M. J. et al. Adult mice generated from induced pluripotent stem cells. Nature 461, 91–94 (2009).
Kang, L., Wang, J., Zhang, Y., Kou, Z. & Gao, S. iPS cells can support full-term development of tetraploid blastocyst-complemented embryos. Cell Stem Cell 5, 135–138 (2009).
Zhao, X. Y. et al. iPS cells produce viable mice through tetraploid complementation. Nature 461, 86–90 (2009). References 32–34 demonstrate the full developmental potential of mouse iPSCs through tetraploid complementation — the most stringent test of developmental potency.
Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008). This was the first demonstration that skin cells from patients can be reprogrammed and differentiated into disease-relevant cell types.
Loh, Y. H. et al. Reprogramming of T cells from human peripheral blood. Cell Stem Cell 7, 15–19 (2010).
Loh, Y. H. et al. Generation of induced pluripotent stem cells from human blood. Blood 113, 5476–5479 (2009).
Rajesh, D. et al. Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 118, 1797–1800 (2011).
Choi, S. M. et al. Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. Blood 118, 1801–1805 (2011). References 38 and 39 first reported the generation of iPSCs from immortalized blood cell lines, providing the opportunity to obtain patient cells from biobanks.
Sommer, C. A. et al. Excision of reprogramming transgenes improves the differentiation potential of iPS cells generated with a single excisable vector. Stem Cells 28, 64–74 (2010).
Si-Tayeb, K. et al. Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors. BMC Dev. Biol. 10, 81 (2010).
Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).
Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G. & Hochedlinger, K. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008). References 42 and 43 were the first reports of reprogramming using vectors that are not integrated into the genome.
Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).
Okita, K. et al. A more efficient method to generate integration-free human iPS cells. Nature Methods 8, 409–412 (2011).
Kaji, K. et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771–775 (2009).
Lacoste, A., Berenshteyn, F. & Brivanlou, A. H. An efficient and reversible transposable system for gene delivery and lineage-specific differentiation in human embryonic stem cells. Cell Stem Cell 5, 332–342 (2009).
Woltjen, K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766–770 (2009).
Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476 (2009).
Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381–384 (2009).
Cho, H. J. et al. Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation. Blood 116, 386–395 (2010).
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).
Seki, T. et al. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7, 11–14 (2010).
Nishimura, K. et al. Development of defective and persistent sendai virus vector: a unique gene delivery/expression system ideal for cell reprogramming. J. Biol. Chem. 286, 4760–4771 (2010).
Yakubov, E., Rechavi, G., Rozenblatt, S. & Givol, D. Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem. Biophys. Res. Commun. 394, 189–193 (2010).
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).
Maehr, R. et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc. Natl Acad. Sci. USA 106, 15768–15773 (2009).
Desponts, C. & Ding, S. Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Methods Mol. Biol. 636, 207–218 (2010).
Li, W. & Ding, S. Small molecules that modulate embryonic stem cell fate and somatic cell reprogramming. Trends Pharmacol. Sci. 31, 36–45 (2010).
Chen, J. et al. BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res. 21, 205–212 (2010).
Zhu, S. et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7, 651–655 (2010).
Aalto-Setala, K., Conklin, B. R. & Lo, B. Obtaining consent for future research with induced pluripotent cells: opportunities and challenges. PLoS Biol. 7, e42 (2009).
Chou, B. K. et al. Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. Cell Res. 21, 518–529 (2011).
Hu, K. et al. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117, e109–e119 (2011).
Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).
Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotech. 28, 848–855 (2010).
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 β cells. Cell Stem Cell 9, 17–23 (2011).
Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nature Cell Biol. 13, 541–549 (2011).
Ghosh, Z. et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 5, e8975 (2010).
Hu, B. Y. et al. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl Acad. Sci. USA 107, 4335–4340 (2010).
Hanna, J. et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc. Natl Acad. Sci. USA 107, 9222–9227 (2010).
Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011). This paper describes the generation of an assay to predict the differentiation efficiency of distinct iPSC clones, providing a tool for quality control of such iPSC clones.
Boulting, G. L. et al. A functionally characterized test set of human induced pluripotent stem cells. Nature Biotech. 29, 279–286 (2011).
Kattman, S. J. et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228–240 (2011).
Liu, L. et al. Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J. Biol. Chem. 285, 19483–19490 (2010).
Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).
Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).
Pasi, C. E. et al. Genomic instability in induced stem cells. Cell Death. Differ. 18, 745–753 (2011).
Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).
Laurent, L. C. et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106–118 (2011).
Hussein, S. M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011). This study demonstrates that reprogramming leads to an increase in copy number variation that is selected against and disappears after prolonged passaging of iPSCs.
Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822–3830 (2009).
Enver, T. et al. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum. Mol. Genet. 14, 3129–3140 (2005).
Watanabe, K. et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nature Biotech. 25, 681–686 (2007).
Svendsen, C. N. et al. A new method for the rapid and long term growth of human neural precursor cells. J. Neurosci. Methods 85, 141–152 (1998).
Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotech. 27, 275–280 (2009).
Soldner, F. et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).
Osakada, F. et al. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J. Cell Sci. 122, 3169–3179 (2009).
Sullivan, G. J. et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 51, 329–335 (2010).
Choi, K. D. et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 27, 559–567 (2009).
Ye, Z. et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114, 5473–5480 (2009).
Taura, D. et al. Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells. FEBS Lett. 583, 1029–1033 (2009).
Friling, S. et al. Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells. Proc. Natl Acad. Sci. USA 106, 7613–7618 (2009).
Hester, M. E. et al. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol. Ther. 19, 1905–1912 (2011).
Panman, L. et al. Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells. Cell Stem Cell 8, 663–675 (2011). References 93–95 describe improvements in the differentiation of iPSCs using lineage-specific transcription factors.
Raya, A. et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53–59 (2009).
Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).
Nguyen, H. N. et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011). Together with references 107 and 151, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.
Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature Rev. Neurosci. 10, 597–609 (2009).
Crawford, T. O. & Pardo, C. A. The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis. 3, 97–110 (1996).
Slaugenhaupt, S. A. et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605 (2001).
Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).
Hotta, A. et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).
Hennekam, R. C. Hutchinson–Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. A 140, 2603–2624 (2006).
Kannankeril, P., Roden, D. M. & Darbar, D. Drug-induced long QT syndrome. Pharmacol. Rev. 62, 760–781 (2010).
Roden, D. M. Drug-induced prolongation of the QT interval. N. Engl. J. Med. 350, 1013–1022 (2004).
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). Together with references 98 and 151, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.
Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004).
Chong, C. R., Chen, X., Shi, L., Liu, J. O. & Sullivan, D. J. Jr. A clinical drug library screen identifies astemizole as an antimalarial agent. Nature Chem. Biol. 2, 415–416 (2006).
Majercak, J. et al. LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 17967–17972 (2006).
Zhou, H. et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 4, 495–504 (2008).
Wysowski, D. K. & Swartz, L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Arch. Intern. Med. 165, 1363–1369 (2005).
Pearson, H. The bitterest pill. Nature 444, 532–533 (2006).
Kola, I. The state of innovation in drug development. Clin. Pharmacol. Ther. 83, 227–230 (2008).
Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).
Tall, A. R., Yvan-Charvet, L. & Wang, N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler. Thromb. Vasc. Biol. 27, 257–260 (2007).
Joy, T. R. & Hegele, R. A. The failure of torcetrapib: what have we learned? Br. J. Pharmacol. 154, 1379–1381 (2008).
Diener, H. C. et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke 39, 1751–1758 (2008).
Erondu, N. et al. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metab. 4, 275–282 (2006).
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Tebbey, P. W. & Rink, C. Target product profile: a renaissance for its definition and use. J. Med. Market. 9, 301–307 (2009).
US Food and Drug Administration. Guidance For Industry And Review Staff: Target Product Profile — A Strategic Development Process Tool. FDA website [online], (2007).
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Frumkin, T. et al. Human embryonic stem cells carrying mutations for severe genetic disorders. In Vitro Cell. Dev. Biol. Anim. 46, 327–336 (2010).
Tropel, P. et al. High-efficiency derivation of human embryonic stem cell lines following pre-implantation genetic diagnosis. In Vitro Cell. Dev. Biol. Anim. 46, 376–385 (2010).
Verlinsky, Y. et al. Human embryonic stem cell lines with genetic disorders. Reprod. Biomed. Online 10, 105–110 (2005).
Mateizel, I. et al. Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum. Reprod. 21, 503–511 (2006).
Marteyn, A. et al. Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell 8, 434–444 (2011).
Deleu, S. et al. Human cystic fibrosis embryonic stem cell lines derived on placental mesenchymal stromal cells. Reprod. Biomed. Online 18, 704–716 (2009).
Somers, A. et al. Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28, 1728–1740 (2010).
Kazuki, Y. et al. Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol. Ther. 18, 386–393 (2010).
Niclis, J. C. et al. Human embryonic stem cell models of Huntington disease. Reprod. Biomed. Online 19, 106–113 (2009).
Zhang, N., An, M. C., Montoro, D. & Ellerby, L. M. Characterization of human Huntington's disease cell model from induced pluripotent stem cells. PLoS Curr. 2, RRN1193 (2010).
Jang, J. et al. Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Ann. Neurol. 70, 402–409 (2011).
Ho, J. C. et al. Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging 3, 380–390 (2011).
Ghodsizadeh, A. et al. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 6, 622–632 (2010).
Agarwal, S. et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).
Batista, L. F. et al. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474, 399–402 (2011).
Tolar, J. et al. Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. J. Invest. Dermatol. 131, 848–856 (2011).
Itoh, M., Kiuru, M., Cairo, M. S. & Christiano, A. M. Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 108, 8797–8802 (2011).
Mitne-Neto, M. et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum. Mol. Genet. 20, 3642–3652 (2011).
Howden, S. E. et al. Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy. Proc. Natl Acad. Sci. USA 108, 6537–6542 (2011).
Liu, G. H. et al. Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472, 221–225 (2011).
Liu, G. H. et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694 (2011).
Khan, I. F. et al. Engineering of human pluripotent stem cells by AAV-mediated gene targeting. Mol. Ther. 18, 1192–1199 (2010).
Tolar, J. et al. Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome). Blood 117, 839–847 (2011).
Lemonnier, T. et al. Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells. Hum. Mol. Genet. 20, 3653–3666 (2011).
Hargus, G. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl Acad. Sci. USA 107, 15921–15926 (2010).
Swistowski, A. et al. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 28, 1893–1904 (2010).
Jin, Z. B. et al. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS ONE 6, e17084 (2011).
Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011). Together with references 98 and 107, this study identifies disease-relevant phenotypes in reprogrammed cells from patients with adult-onset diseases.
Zhang, S. et al. Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum. Mol. Genet. 20, 3176–3187 (2011).
Zou, J. et al. Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting. Blood 117, 5561–5572 (2011).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotech. 26, 101–106 (2008).
Anokye-Danso, F. et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8, 376–388 (2011).
Zhou, W. & Freed, C. R. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27, 2667–2674 (2009).
Jia, F. et al. A nonviral minicircle vector for deriving human iPS cells. Nature Methods 7, 197–199 (2010).
Miyoshi, N. et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8, 633–638 (2011).
Esteban, M. A. et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 6, 71–79 (2010).
Lin, T. et al. A chemical platform for improved induction of human iPSCs. Nature Methods 6, 805–808 (2009).
Mali, P. et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28, 713–720 (2010).
Haase, A. et al. Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell 5, 434–441 (2009).
Eminli, S. et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nature Genet. 41, 968–976 (2009).
Giorgetti, A. et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5, 353–357 (2009).
Lagarkova, M. A. et al. Induction of pluripotency in human endothelial cells resets epigenetic profile on genome scale. Cell Cycle 9, 937–946 (2010).
Sun, N. et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc. Natl Acad. Sci. USA 106, 15720–15725 (2009).
Aoki, T. et al. Generation of induced pluripotent stem cells from human adipose-derived stem cells without c-MYC. Tissue Eng. Part A 16, 2197–2206 (2010).
Aasen, T. et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature Biotech. 26, 1276–1284 (2008).
Carey, B. W. et al. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc. Natl Acad. Sci. USA 106, 157–162 (2009).
Li, W. et al. Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells 27, 2992–3000 (2009).
Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 28 Aug 2009 (doi:10.1038/nature08436).
Ruiz, S. et al. High-efficient generation of induced pluripotent stem cells from human astrocytes. PLoS ONE 5, e15526 (2010).
Liu, H., Ye, Z., Kim, Y., Sharkis, S. & Jang, Y. Y. Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes. Hepatology 51, 1810–1819 (2010).
Li, C. et al. Pluripotency can be rapidly and efficiently induced in human amniotic fluid-derived cells. Hum. Mol. Genet. 18, 4340–4349 (2009).
Zhao, H. X. et al. Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation 80, 123–129 (2010).
The authors would like to especially thank S. Irion, E. Vaisberg, I. Griswold-Prenner and C. Johnson for their crucial input and help with writing the manuscript. Special thanks to A. Rosenthal for his help in editing and integrating the manuscript, and M. Smith and B. Keon for their help with the graphic design.
Marica Grskovic and Ashkan Javaherian are both employed by iPierian, and Berta Strulovici is a former employee. George Q. Daley is on the scientific advisory board of iPierian. All co-authors hold equity in the company, which uses induced pluripotent stem cells to develop drugs against neurodegenerative diseases.
- Embryonic stem cells
(ESCs). Pluripotent cells derived from a pre-implantation-stage embryo. These cells are capable of dividing without differentiating for a prolonged period in culture.
- Induced pluripotent stem cells
(iPSCs). Pluripotent cells derived from differentiated somatic cells through treatment with exogenous factors.
- Disease phenotype
A molecular, cellular or functional manifestation of a disease in patient-derived cells.
- Pluripotent stem cells
(PSCs). Undifferentiated cells that have the ability to self-renew and the potential to differentiate into cells of the three primary germ layers: endoderm, mesoderm or ectoderm.
- Embryoid bodies
Aggregates of cells derived from pluripotent cells, formed by growing pluripotent cells in suspension in the absence of self-renewal-promoting factors. Following their aggregation, these cells differentiate into various differentiated cell types partly recapitulating early embryonic development.
The process by which a differentiated somatic cell acquires the features of a pluripotent stem cell or a differentiated cell of a different cell type.
- Spinal muscular atrophy
A monogenic neurodevelopmental disorder in which a reduced level of survival of motor neuron (SMN) protein leads to the degeneration of motor neurons during childhood.
A heritable change in gene expression that is not caused by the DNA sequence.
- Copy number variations
Duplications or deletions in the genome that lead to variability in the number of genes.
- LEOPARD syndrome
An autosomal dominant multisystem disease caused by a mutation in the gene encoding protein tyrosine phosphatase non-receptor type 11. The disease affects the skin as well as the skeletal and cardiovascular systems.
- QT interval
A measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart.
About this article
Cite this article
Grskovic, M., Javaherian, A., Strulovici, B. et al. Induced pluripotent stem cells — opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 10, 915–929 (2011). https://doi.org/10.1038/nrd3577
Comparison of osteogenic differentiation potential of induced pluripotent stem cells and buccal fat pad stem cells on 3D-printed HA/β-TCP collagen-coated scaffolds
Cell and Tissue Research (2021)
Scientific Reports (2020)
Metabolomic profiles of induced pluripotent stem cells derived from patients with rheumatoid arthritis and osteoarthritis
Stem Cell Research & Therapy (2019)
Scientific Reports (2019)
Scientific Reports (2019)