Perspective

Induced pluripotent stem cells: opportunities as research and development tools in 21st century drug discovery

Pfizer Regenerative Medicine, 620 Memorial Drive, Cambridge, MA 02139, USA

Search for more papers by this author

John D McNeish

† Author for correspondence

Search for more papers by this author

Email the corresponding author at john.d.mcneish@pfizer.com

Published Online:15 Jul 2010https://doi.org/10.2217/rme.10.36

View article

Abstract

Pluripotent embryonic stem cells (ESCs), when compared with transformed, primary or engineered cells, have unique characteristics and advantages that have resulted in the development of important cell-based tools in modern drug discovery. However, a key limitation has been the availability of human ESCs from patients with specific medical needs and the broad range of genetic variation represented worldwide. Induced pluripotent stem (iPS) cells are derived from somatic cells that are reprogrammed to a pluripotent stem cell state and have functional characteristics similar to ESCs. The demonstration that human iPS cells can be derived, with relative ease, through the introduction of transcription factor combinations has allowed the generation of disease-specific iPS cell lines. Therefore, iPS cell technology may deliver robust, human pluripotent cell lines from a wide range of clinical phenotypes and genotypes. Although human iPS cell technology is still a new tool in drug discovery, the promise that this technology will impact the discovery of new therapies can be projected based on the uptake of stem cell applications in biopharmaceutical sciences. Here, the near-term opportunities that iPS cells may deliver to drug discoverers to generate and test hypotheses will be discussed, with a focus on the specific strengths and weaknesses of iPS cell technology. Finally, the future perspective will address novel opportunities iPS cells could uniquely deliver to the preclinical development of new drug therapies.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

1 Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126(4),663–676 (2006).▪▪ First paper to describe the reprogramming of a somatic cell into a pluripotent stem cell through the overexpression of four transcription factors.
Medline CASGoogle Scholar
2 Baker M: iPS cells: potent stuff. Nat. Methods7(1),17–19 (2009).
Google Scholar
3 Woltjen K, Michael IP, Mohseni P et al.: Piggybac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature458(7239),766–770 (2009).
Medline CASGoogle Scholar
4 Soldner F, Hockemeyer D, Beard C et al.: Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell136(5),964–977 (2009).
Medline CASGoogle Scholar
5 Sommer CA, Sommer AG, Longmire TA et al.: Excision of reprogramming transgenes improves the differentiation potential of iPS cells generated with a single excisable vector. Stem Cells28(1),64–74 (2009).
Google Scholar
6 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S: Generation of mouse induced pluripotent stem cells without viral vectors. Science322(5903),949–953 (2008).
Medline CASGoogle Scholar
7 Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K: Induced pluripotent stem cells generated without viral integration. Science322(5903),945–949 (2008).
Medline CASGoogle Scholar
8 Yu J, Hu K, Smuga-Otto K et al.: Human induced pluripotent stem cells free of vector and transgene sequences. Science324(5928),797–801 (2009).
Medline CASGoogle Scholar
9 Zhou H, Wu S, Joo JY et al.: Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell4(5),381–384 (2009).
Medline CASGoogle Scholar
10 Kim D, Kim CH, Moon JI et al.: Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell4(6),472–476 (2009).
Medline CASGoogle Scholar
11 Ichida JK, Blanchard J, Lam K et al.: A small-molecule inhibitor of TGF-β signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell5(5),491–503 (2009).
Medline CASGoogle Scholar
12 Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S: A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell2(6),525–528 (2008).
Medline CASGoogle Scholar
13 Lin T, Ambasudhan R, Yuan X et al.: A chemical platform for improved induction of human iPSCs. Nat. Methods6(11),805–808 (2009).
Medline CASGoogle Scholar
14 Lyssiotis CA, Foreman RK, Staerk J et al.: Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of KLF4. Proc. Natl Acad. Sci. USA106(22),8912–8917 (2009).
MedlineGoogle Scholar
15 Maherali N, Hochedlinger K: TGF-β signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and c-myc. Curr. Biol.19(20),1718–1723 (2009).
Medline CASGoogle Scholar
16 Huangfu D, Maehr R, Guo W et al.: Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol.26(7),795–797 (2008).
Medline CASGoogle Scholar
17 Rodriguez-Piza I, Richaud-Patin Y, Vassena R et al.: Reprogramming of human fibroblasts to induced pluripotent stem cells under xeno-free conditions. Stem Cells28(1),36–44 (2009).
Google Scholar
18 Takahashi K, Narita M, Yokura M, Ichisaka T, Yamanaka S: Human induced pluripotent stem cells on autologous feeders. PLoS One4(12),e8067 (2009).
MedlineGoogle Scholar
19 Stadtfeld M, Maherali N, Borkent M, Hochedlinger K: A reprogrammable mouse strain from gene-targeted embryonic stem cells. Nat. Methods7(1),53–55 (2010).
Medline CASGoogle Scholar
20 Carey BW, Markoulaki S, Beard C, Hanna J, Jaenisch R: Single-gene transgenic mouse strains for reprogramming adult somatic cells. Nat. Methods7(1),56–59 (2010).
Medline CASGoogle Scholar
21 Lee H, Park J, Forget BG, Gaines P: Induced pluripotent stem cells in regenerative medicine: an argument for continued research on human embryonic stem cells. Regen. Med.4(5),759–769 (2009).▪▪ Addresses the issues related to human induced pluripotent stem (iPS) and embryonic stem cells, which includes support for continued research and development of new pluripotent stem cell lines using both technologies.
Google Scholar
22 McNeish JD: Stem cells as screening tools in drug discovery. Curr. Opin. Pharmacol.7(5),515–520 (2007).
Medline CASGoogle Scholar
23 Takahashi K, Tanabe K, Ohnuki M et al.: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131(5),861–872 (2007).
Medline CASGoogle Scholar
24 Yu J, Vodyanik MA, Smuga-Otto K et al.: Induced pluripotent stem cell lines derived from human somatic cells. Science318(5858),1917–1920 (2007).
Medline CASGoogle Scholar
25 Chin MH, Mason MJ, Xie W et al.: Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell5(1),111–123 (2009).
Medline CASGoogle Scholar
26 Wilson KD, Venkatasubrahmanyam S, Jia F, Sun N, Butte AJ, Wu JC: MicroRNA profiling of human-induced pluripotent stem cells. Stem Cells Dev.18(5),749–758 (2009).
Medline CASGoogle Scholar
27 Kay GF, Penny GD, Patel D, Ashworth A, Brockdorff N, Rastan S: Expression of xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell72(2),171–182 (1993).
Medline CASGoogle Scholar
28 Maherali N, Sridharan R, Xie W et al.: Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell1(1),55–70 (2007).
Medline CASGoogle Scholar
29 Novak K: Stem cell therapies: California dreamin’? Cell140(1),10–12 (2010).
Medline CASGoogle Scholar
30 Sacca R, Engle SJ, Qin W, Stock JL, McNeish JD: Genetically engineered mouse models in drug discovery research. Methods Mol. Biol.602,37–54 (2010).
Medline CASGoogle Scholar
31 Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R: The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol.87,27–45 (1985).
Medline CASGoogle Scholar
32 Gorba T, Allsopp TE: Pharmacological potential of embryonic stem cells. Pharmacol. Res.47(4),269–278 (2003).
Medline CASGoogle Scholar
33 McNeish J: Embryonic stem cells in drug discovery. Nat. Rev. Drug Discov.3(1),70–80 (2004).
Medline CASGoogle Scholar
34 Pouton CW, Haynes JM: Embryonic stem cells as a source of models for drug discovery. Nat. Rev. Drug Discov.6(8),605–616 (2007).
Medline CASGoogle Scholar
35 Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel CA: Deficiency of the stress kinase p38a results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J. Exp. Med.191(5),859–870 (2000).
Medline CASGoogle Scholar
36 McNeish J, Roach M, Hambor J et al.: High-throughput chemical library screening in embryonic stem cell-derived neurons identifies potentiators of AMPA-type glutamate receptors. J. Biol. Chem.285(22),17209–17217 (2010).
Medline CASGoogle Scholar
37 Paquette JA, Kumpf SW, Streck RD, Thomson JJ, Chapin RE, Stedman DB: Assessment of the embryonic stem cell test and application and use in the pharmaceutical industry. Birth Defects Res. B Dev. Reprod. Toxicol.83(2),104–111 (2008).
Medline CASGoogle Scholar
38 Niclis JC, Trounson, AO, Dottori M et al.: Human embryonic stem cell models of Huntington disease. Reprod. Biomed. Online19(1),106–113 (2009).
Medline CASGoogle Scholar
39 Li W, Wei W, Zhu S et al.: Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell4(1),16–19 (2009).
MedlineGoogle Scholar
40 Wu Z, Chen J, Ren J et al.: Generation of pig induced pluripotent stem cells with a drug-inducible system. J. Mol. Cell Biol.1(1),46–54 (2009).
Medline CASGoogle Scholar
41 Ezashi T, Telugu BP, Alexenko AP, Sachdev S, Sinha S, Roberts RM: Derivation of induced pluripotent stem cells from pig somatic cells. Proc. Natl Acad. Sci. USA106(27),10993–10998 (2009).
Medline CASGoogle Scholar
42 Esteban MA, Xu J, Yang J et al.: Generation of induced pluripotent stem cell lines from Tibetan miniature pig. J. Biol. Chem.284(26),17634–17640 (2009).
Medline CASGoogle Scholar
43 Liu H, Zhu F, Yong J et al.: Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell3(6),587–590 (2008).
Medline CASGoogle Scholar
44 Shimada H, Nakada A, Hashimoto Y, Shigeno K, Shionoya Y, Nakamura T: Generation of canine induced pluripotent stem cells by retroviral transduction and chemical inhibitors. Mol. Reprod. Dev.77(1),2 (2010).
Medline CASGoogle Scholar
45 Aasen T, Raya A, Barrero MJ et al.: Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol.26(11),1276–1284 (2008).
Medline CASGoogle Scholar
46 Giorgetti A, Montserrat N, Aasen T et al.: Generation of induced pluripotent stem cells from human cord blood using Oct4 and Sox2. Cell Stem Cell5(4),353–357 (2009).
Medline CASGoogle Scholar
47 Haase A, Olmer R, Schwanke K et al.: Generation of induced pluripotent stem cells from human cord blood. Cell Stem Cell5(4),434–441 (2009).
Medline CASGoogle Scholar
48 Sun N, Panetta NJ, Gupta DM et al.: Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc. Natl Acad. Sci. USA106(37),15720–15725 (2009).
Medline CASGoogle Scholar
49 Osafune K, Caron L, Borowiak M et al.: Marked differences in differentiation propensity among human embryonic stem cell lines. Nat. Biotechnol.26(3),313–315 (2008).▪ An important paper demonstrating that all pluripotent stem cells will have unique functional characteristics, which need to be considered in advance of experimental design.
Medline CASGoogle Scholar
50 Choi KD, Yu J, Smuga-Otto K et al.: Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells27(3),559–567 (2009).
Medline CASGoogle Scholar
51 Colman A, Dreesen O: Induced pluripotent stem cells and the stability of the differentiated state. EMBO Rep.10(7),714–721 (2009).
Medline CASGoogle Scholar
52 D’Amour KA, Bang AG, Eliazer S et al.: Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol.24(11),1392–1401 (2006).
MedlineGoogle Scholar
53 Song Z, Cai J, Liu Y et al.: Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res.19(11),1233–1242 (2009).
MedlineGoogle Scholar
54 Kehat I, Kenyagin-Karsenti D, Snir M et al.: Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest.108(3),407–414 (2001).
Medline CASGoogle Scholar
55 Maehr R, Chen S, Snitow M et al.: Generation of pluripotent stem cells from patients with Type 1 diabetes. Proc. Natl Acad. Sci. USA106(37),15768–15773 (2009).
Medline CASGoogle Scholar
56 Chan EM, Ratanasirintrawoot S, Park IH et al.: Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat. Biotechnol.27(11),1033–1037 (2009).
Medline CASGoogle Scholar
57 Laurent LC, Nievergelt CM, Lynch C et al.: Restricted ethnic diversity in human embryonic stem cell lines. Nat. Methods7(1),6–7 (2010).
Medline CASGoogle Scholar
58 Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L: Highly efficient neural conversion of human ES and iPS cells by dual inhibition of smad signaling. Nat. Biotechnol.27(3),275–280 (2009).
Medline CASGoogle Scholar
59 Ebert AD, Yu J, Rose FF Jr et al.: Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature457(7227),277–280 (2009).▪▪ One of the first to demonstrate functional phenotypes in patient-derived iPS cells. The iPS cells were derived from patients with spinal muscle atrophy and the differentiated iPS cell lines demonstrated relative motor neuron loss over time and expected responsiveness to small therapeutics.
Medline CASGoogle Scholar
60 Lamba DA, Mcusic A, Hirata RK, Wang PR, Russell D, Reh TA: Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS One5(1),e8763 (2010).
MedlineGoogle Scholar
61 Buchholz DE, Hikita ST, Rowland TJ et al.: Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells27(10),2427–2434 (2009).
Medline CASGoogle Scholar
62 Taura D, Noguchi M, Sone M et al.: Adipogenic differentiation of human induced pluripotent stem cells: comparison with that of human embryonic stem cells. FEBS Lett.583(6),1029–1033 (2009).
Medline CASGoogle Scholar
63 Sullivan GJ, Hay DC, Park IH et al.: Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology51(1),329–335 (2010).
Medline CASGoogle Scholar
64 Si-Tayeb K, Noto FK, Nagaoka M et al.: Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology51(1),297–305 (2010).
Medline CASGoogle Scholar
65 Yokoo N, Baba S, Kaichi S et al.: The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem. Biophys. Res. Commun.387(3),482–488 (2009).▪ Demonstrates that functional cardiomyocytes can be derived from iPS cells and these cells respond in a predicted manner pharmacologically.
Medline CASGoogle Scholar
66 Zwaka TP, Thomson JA: Homologous recombination in human embryonic stem cells. Nat. Biotechnol.21(3),319–321 (2003).
Medline CASGoogle Scholar
67 Hockemeyer D, Soldner F, Beard C et al.: Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat. Biotechnol.27(9),851–857 (2009).
Medline CASGoogle Scholar
68 Zou J, Maeder ML, Mali P et al.: Gene targeting of a disease-related gene in human induced pluripotent stem and embryonic stem cells. Cell Stem Cell5(1),97–110 (2009).
Medline CASGoogle Scholar
69 Root DE, Hacohen N, Hahn WC, Lander ES, Sabatini DM: Genome-scale loss-of-function screening with a lentiviral RNAi library. Nat. Methods3(9),715–719 (2006).
Medline CASGoogle Scholar
70 Saha K, Jaenisch R: Technical challenges in using human induced pluripotent stem cells to model disease. Cell Stem Cell5(6),584–595 (2009).▪▪ A comprehensive review of the strengths and weaknesses of iPS cells for use as preclinical disease models. This article also notes advances in technologies that may prove effective in overcoming limitations in current iPS cell-based applications.
Medline CASGoogle Scholar
71 Guengerich FP: Cytochrome p450 and chemical toxicology. Chem. Res. Toxicol.21(1),70–83 (2008).
Medline CASGoogle Scholar
72 Zhou SF: Polymorphism of human cytochrome p450 2D6 and its clinical significance: part I. Clin. Pharmacokinet.48(11),689–723 (2009).
Medline CASGoogle Scholar
73 Gwathmey JK, Tsaioun K, Hajjar RJ: Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates. Expert Opin. Drug Metab. Toxicol.5(6),647–660 (2009).
Medline CASGoogle Scholar
74 Huikuri HV, Castellanos A, Myerburg RJ: Sudden death due to cardiac arrhythmias. N. Engl. J. Med.345(20),1473–1482 (2001).
Medline CASGoogle Scholar
75 Splawski I, Shen J, Timothy KW et al.: Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.Circulation102(10),1178–1185 (2000).
Medline CASGoogle Scholar
76 Lin G, Xie Y, Ouyang Q et al.: HLA-matching potential of an established human embryonic stem cell bank in China. Cell Stem Cell5(5),461–465 (2009).
Medline CASGoogle Scholar
77 Condic ML, Rao M: Regulatory issues for personalized pluripotent cells. Stem Cells26(11),2753–2758 (2008).
Medline CASGoogle Scholar
78 Li Y, Zeng H, Xu RH, Liu B, Li Z: Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical responses against colon cancer. Stem Cells27(12),3103–3111 (2009).
Medline CASGoogle Scholar
101 Cellular Dynamics www.cellulardynamics.com
Google Scholar
102 Diagnostics 2009: Moving towards personalized medicine www.pwc.com
Google Scholar

Vol. 5, No. 4

Metrics

Downloaded 501 times

History

Published online 15 July 2010

Published in print July 2010

Information

Keywords

Acknowledgements

The authors would like to thank L Daheron (HSCI) and S Engle (Pfizer) for helpful discussions and contribution of unpublished data.

Financial & competing interests disclosure

The authors are employees of Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download