Skip to main content
SpringerLink
Log in

Stem Cells for Drug Screening

  • Chapter
  • First Online:
Recent Advances in Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

  • 918 Accesses

Abstract

Stem cells (SCs) are defined by two major features, self-renewal and pluripotency. Moreover, SCs are classified as embryonic (ESC), adult (ASC), and induced pluripotent (iPSC) stem cells. SCs are capable of differentiation into various types of cells, and have therefore been applied to investigations of genome and cellular functions, genetic therapy, toxicity, and drug screening. Drug screening using stem cells is useful for investigating developmental toxicity, tissue specificity, and disease-specific responses. The embryonic stem cell test (EST) was proposed to assess undesirable effects during development, and was validated by the European Center for Validation of Alternative Methods (ECVAM). The EST measures cytotoxic and inhibitory effects of chemicals during the developmental process. The human ES-EST can overcome interspecies differences and decrease false-negative effects. Differentiated cardiomyocytes and hepatocytes derived from SCs are capable of assessing tissue-specific toxicity of tested drugs. Human iPSCs that originate from patients are useful for disease-specific and personalized drug screening in pharmaceutical therapy. Drug screening using SCs offers various chances to evaluate developmental, tissue-specific, and disease-specific toxicities.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Theise ND, Krause DS. Toward a new paradigm of cell plasticity. Leukemia. 2002;16(4):542–8. doi:10.1038/sj.leu.2402445.

    Article  CAS  PubMed  Google Scholar 

  2. Nagy A, Gocza E, Diaz EM, Prideaux VR, Ivanyi E, Markkula M, Rossant J. Embryonic stem cells alone are able to support fetal development in the mouse. Development. 1990;110(3):815–21.

    CAS  PubMed  Google Scholar 

  3. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

    Article  CAS  PubMed  Google Scholar 

  4. Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, Lendahl U, Frisen J. Generalized potential of adult neural stem cells. Science. 2000;288(5471):1660–3.

    Article  CAS  PubMed  Google Scholar 

  5. Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci U S A. 2002;99(12):8078–83. doi:10.1073/pnas.122210699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Toma JG, Akhavan M, Fernandes KJ, Barnabe-Heider F, Sadikot A, Kaplan DR, Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001;3(9):778–84. doi:10.1038/ncb0901-778.

    Article  CAS  PubMed  Google Scholar 

  7. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28. doi:10.1089/107632701300062859.

    Article  CAS  PubMed  Google Scholar 

  8. Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci U S A. 1999;96(25):14482–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A. 2003;100(5):2426–31. doi:10.1073/pnas.0536882100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. French AJ, Adams CA, Anderson LS, Kitchen JR, Hughes MR, Wood SH. Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells. 2008;26(2):485–93. doi:10.1634/stemcells.2007-0252.

    Article  CAS  PubMed  Google Scholar 

  11. Hurlbut WB. Altered nuclear transfer: a way forward for embryonic stem cell research. Stem Cell Rev. 2005;1(4):293–300. doi:10.1385/SCR:1:4:293.

    Article  PubMed  Google Scholar 

  12. Cowan CA, Atienza J, Melton DA, Eggan K. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science. 2005;309(5739):1369–73. doi:10.1126/science.1116447.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024.

    Article  CAS  PubMed  Google Scholar 

  14. Kang KS, Trosko JE. Stem cells in toxicology: fundamental biology and practical considerations. Toxicol Sci. 2011;120 Suppl 1:S269–89. doi:10.1093/toxsci/kfq370.

    Article  CAS  PubMed  Google Scholar 

  15. Hartung T. Food for thought … on alternative methods for cosmetics safety testing. ALTEX. 2008;25(3):147–62.

    PubMed  Google Scholar 

  16. Basketter DA, Clewell H, Kimber I, Rossi A, Blaauboer B, Burrier R, Daneshian M, Eskes C, Goldberg A, Hasiwa N, Hoffmann S, Jaworska J, Knudsen TB, Landsiedel R, Leist M, Locke P, Maxwell G, McKim J, McVey EA, Ouedraogo G, Patlewicz G, Pelkonen O, Roggen E, Rovida C, Ruhdel I, Schwarz M, Schepky A, Schoeters G, Skinner N, Trentz K, Turner M, Vanparys P, Yager J, Zurlo J, Hartung T. A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing—t4 report*. ALTEX. 2012;29(1):3–91.

    Article  PubMed  Google Scholar 

  17. Hartung T, Hoffmann S. Food for thought … on in silico methods in toxicology. ALTEX. 2009;26(3):155–66.

    PubMed  Google Scholar 

  18. Hofer T, Gerner I, Gundert-Remy U, Liebsch M, Schulte A, Spielmann H, Vogel R, Wettig K. Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation. Arch Toxicol. 2004;78(10):549–64. doi:10.1007/s00204-004-0577-9.

    Article  PubMed  CAS  Google Scholar 

  19. Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tahti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol. 2011;85(5):367–485. doi:10.1007/s00204-011-0693-2.

    Article  CAS  PubMed  Google Scholar 

  20. Louisse J, Verwei M, Woutersen RA, Blaauboer BJ, Rietjens IM. Toward in vitro biomarkers for developmental toxicity and their extrapolation to the in vivo situation. Expert Opin Drug Metab Toxicol. 2012;8(1):11–27. doi:10.1517/17425255.2012.639762.

    Article  CAS  PubMed  Google Scholar 

  21. Spielmann H. Predicting the risk of developmental toxicity from in vitro assays. Toxicol Appl Pharmacol. 2005;207(2 Suppl):375–80. doi:10.1016/j.taap.2005.01.049.

    Article  PubMed  CAS  Google Scholar 

  22. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.

    Article  CAS  PubMed  Google Scholar 

  23. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC. A nonviral minicircle vector for deriving human iPS cells. Nat Methods. 2010;7(3):197–9. doi:10.1038/nmeth.1426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K. Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell. 2010;7(1):11–4. doi:10.1016/j.stem.2010.06.003.

    Article  CAS  PubMed  Google Scholar 

  26. 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. 2010;394(1):189–93. doi:10.1016/j.bbrc.2010.02.150.

    Article  CAS  PubMed  Google Scholar 

  27. Narsinh KH, Jia F, Robbins RC, Kay MA, Longaker MT, Wu JC. Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nat Protoc. 2011;6(1):78–88. doi:10.1038/nprot.2010.173.

    Article  CAS  PubMed  Google Scholar 

  28. Scott CW, Peters MF, Dragan YP. Human induced pluripotent stem cells and their use in drug discovery for toxicity testing. Toxicol Lett. 2013;219(1):49–58. doi:10.1016/j.toxlet.2013.02.020.

    Article  CAS  PubMed  Google Scholar 

  29. Lieu DK, Liu J, Siu CW, McNerney GP, Tse HF, Abu-Khalil A, Huser T, Li RA. Absence of transverse tubules contributes to non-uniform Ca(2+) wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 2009;18(10):1493–500. doi:10.1089/scd.2009.0052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature. 2012;482(7384):216–20. doi:10.1038/nature10821.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jozefczuk J, Prigione A, Chavez L, Adjaye J. Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation. Stem Cells Dev. 2011;20(7):1259–75. doi:10.1089/scd.2010.0361.

    Article  CAS  PubMed  Google Scholar 

  32. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107(21):2733–40. doi:10.1161/01.CIR.0000068356.38592.68.

    Article  CAS  PubMed  Google Scholar 

  33. Kmiec Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol. 2001;161:III–XIII, 1–151.

    Google Scholar 

  34. Pellizzer C, Bremer S, Hartung T. Developmental toxicity testing from animal towards embryonic stem cells. ALTEX. 2005;22(2):47–57.

    PubMed  Google Scholar 

  35. Hong EJ, Choi Y, Yang H, Kang HY, Ahn C, Jeung EB. Establishment of a rapid drug screening system based on embryonic stem cells. Environ Toxicol Pharmacol. 2015;39(1):327–38. doi:10.1016/j.etap.2014.12.003.

    Article  CAS  PubMed  Google Scholar 

  36. Buesen R, Genschow E, Slawik B, Visan A, Spielmann H, Luch A, Seiler A. Embryonic stem cell test remastered: comparison between the validated EST and the new molecular FACS-EST for assessing developmental toxicity in vitro. Toxicol Sci. 2009;108(2):389–400. doi:10.1093/toxsci/kfp012.

    Article  CAS  PubMed  Google Scholar 

  37. Le Coz F, Suzuki N, Nagahori H, Omori T, Saito K. Hand1-Luc embryonic stem cell test (Hand1-Luc EST): a novel rapid and highly reproducible in vitro test for embryotoxicity by measuring cytotoxicity and differentiation toxicity using engineered mouse ES cells. J Toxicol Sci. 2015;40(2):251–61. doi:10.2131/jts.40.251.

    Article  PubMed  Google Scholar 

  38. Scholz G, Genschow E, Pohl I, Bremer S, Paparella M, Raabe H, Southee J, Spielmann H. Prevalidation of the embryonic stem cell test (EST)-a new in vitro embryotoxicity test. Toxicol In Vitro. 1999;13(4–5):675–81.

    Article  CAS  PubMed  Google Scholar 

  39. Strubing C, Ahnert-Hilger G, Shan J, Wiedenmann B, Hescheler J, Wobus AM. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech Dev. 1995;53(2):275–87.

    Article  CAS  PubMed  Google Scholar 

  40. zur Nieden NI, Kempka G, Ahr HJ. In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation. 2003;71(1):18–27. doi:10.1046/j.1432-0436.2003.700602.x.

    Article  CAS  PubMed  Google Scholar 

  41. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002;91(3):189–201.

    Article  CAS  PubMed  Google Scholar 

  42. Scholz G, Pohl I, Genschow E, Klemm M, Spielmann H. Embryotoxicity screening using embryonic stem cells in vitro: correlation to in vivo teratogenicity. Cells Tissues Organs. 1999;165(3–4):203–11. doi:10.1159/000016700.

    Article  CAS  PubMed  Google Scholar 

  43. Rohwedel J, Guan K, Hegert C, Wobus AM. Embryonic stem cells as an in vitro model for mutagenicity, cytotoxicity and embryotoxicity studies: present state and future prospects. Toxicol In Vitro. 2001;15(6):741–53.

    Article  CAS  PubMed  Google Scholar 

  44. Genschow E, Spielmann H, Scholz G, Pohl I, Seiler A, Clemann N, Bremer S, Becker K. Validation of the embryonic stem cell test in the international ECVAM validation study on three in vitro embryotoxicity tests. Altern Lab Anim. 2004;32(3):209–44.

    CAS  PubMed  Google Scholar 

  45. Tandon S, Jyoti S. Embryonic stem cells: an alternative approach to developmental toxicity testing. J Pharm Bioallied Sci. 2012;4(2):96–100. doi:10.4103/0975-7406.94808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Suzuki N, Ando S, Yamashita N, Horie N, Saito K. Evaluation of novel high-throughput embryonic stem cell tests with new molecular markers for screening embryotoxic chemicals in vitro. Toxicol Sci. 2011;124(2):460–71. doi:10.1093/toxsci/kfr250.

    Article  CAS  PubMed  Google Scholar 

  47. Cross JC, Flannery ML, Blanar MA, Steingrimsson E, Jenkins NA, Copeland NG, Rutter WJ, Werb Z. Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development. Development. 1995;121(8):2513–23.

    CAS  PubMed  Google Scholar 

  48. Wang DZ, Reiter RS, Lin JL, Wang Q, Williams HS, Krob SL, Schultheiss TM, Evans S, Lin JJ. Requirement of a novel gene, Xin, in cardiac morphogenesis. Development. 1999;126(6):1281–94.

    CAS  PubMed  Google Scholar 

  49. Suzuki N, Ando S, Sumida K, Horie N, Saito K. Analysis of altered gene expression specific to embryotoxic chemical treatment during embryonic stem cell differentiation into myocardiac and neural cells. J Toxicol Sci. 2011;36(5):569–85.

    Article  CAS  PubMed  Google Scholar 

  50. Suzuki N, Yamashita N, Koseki N, Yamada T, Kimura Y, Aiba S, Toyoizumi T, Watanabe M, Ohta R, Tanaka N, Saito K. Assessment of technical protocols for novel embryonic stem cell tests with molecular markers (Hand1- and Cmya1-ESTs): a preliminary cross-laboratory performance analysis. J Toxicol Sci. 2012;37(4):845–51.

    Article  CAS  PubMed  Google Scholar 

  51. Marx-Stoelting P, Adriaens E, Ahr HJ, Bremer S, Garthoff B, Gelbke HP, Piersma A, Pellizzer C, Reuter U, Rogiers V, Schenk B, Schwengberg S, Seiler A, Spielmann H, Steemans M, Stedman DB, Vanparys P, Vericat JA, Verwei M, van der Water F, Weimer M, Schwarz M. A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop. Altern Lab Anim. 2009;37(3):313–28.

    CAS  PubMed  Google Scholar 

  52. Piersma AH. Validation of alternative methods for developmental toxicity testing. Toxicol Lett. 2004;149(1–3):147–53. doi:10.1016/j.toxlet.2003.12.029.

    Article  CAS  PubMed  Google Scholar 

  53. Fassler R, Rohwedel J, Maltsev V, Bloch W, Lentini S, Guan K, Gullberg D, Hescheler J, Addicks K, Wobus AM. Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta 1 integrin. J Cell Sci. 1996;109(Pt 13):2989–99.

    PubMed  Google Scholar 

  54. Bremer S, Worth AP, Paparella M, Bigot K, Kolossov E, Fleischmann BK, Hescheler J, Balls M. Establishment of an in vitro reporter gene assay for developmental cardiac toxicity. Toxicol In Vitro. 2001;15(3):215–23.

    Article  CAS  PubMed  Google Scholar 

  55. Pamies D, Vicente-Salar N, Sogorb MA, Roche E, Reig JA. Specific effect of 5-fluorouracil on alpha-fetoprotein gene expression during the in vitro mouse embryonic stem cell differentiation. Int J Toxicol. 2010;29(3):297–304. doi:10.1177/1091581810366312.

    Article  CAS  PubMed  Google Scholar 

  56. van Dartel DA, Pennings JL, de la Fonteyne LJ, Brauers KJ, Claessen S, van Delft JH, Kleinjans JC, Piersma AH. Evaluation of developmental toxicant identification using gene expression profiling in embryonic stem cell differentiation cultures. Toxicol Sci. 2011;119(1):126–34. doi:10.1093/toxsci/kfq291.

    Article  PubMed  CAS  Google Scholar 

  57. van Dartel DA, Pennings JL, Robinson JF, Kleinjans JC, Piersma AH. Discriminating classes of developmental toxicants using gene expression profiling in the embryonic stem cell test. Toxicol Lett. 2011;201(2):143–51. doi:10.1016/j.toxlet.2010.12.019.

    Article  PubMed  CAS  Google Scholar 

  58. Osman AM, van Dartel DA, Zwart E, Blokland M, Pennings JL, Piersma AH. Proteome profiling of mouse embryonic stem cells to define markers for cell differentiation and embryotoxicity. Reprod Toxicol. 2010;30(2):322–32. doi:10.1016/j.reprotox.2010.05.084.

    Article  CAS  PubMed  Google Scholar 

  59. Mose T, Mathiesen L, Karttunen V, Nielsen JK, Sieppi E, Kummu M, Morck TA, Myohanen K, Partanen H, Vahakangas K, Knudsen LE, Myllynen P. Meta-analysis of data from human ex vivo placental perfusion studies on genotoxic and immunotoxic agents within the integrated European project NewGeneris. Placenta. 2012;33(5):433–9. doi:10.1016/j.placenta.2012.02.004.

    Article  CAS  PubMed  Google Scholar 

  60. Myllynen P, Mathiesen L, Weimer M, Annola K, Immonen E, Karttunen V, Kummu M, Morck TJ, Nielsen JK, Knudsen LE, Vahakangas K. Preliminary interlaboratory comparison of the ex vivo dual human placental perfusion system. Reprod Toxicol. 2010;30(1):94–102. doi:10.1016/j.reprotox.2010.04.006.

    Article  CAS  PubMed  Google Scholar 

  61. Myllynen P, Vahakangas K. An examination of whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J Pharmacol Toxicol Methods. 2002;48(3):131–8. doi:10.1016/S1056-8719(03)00038-8.

    Article  CAS  PubMed  Google Scholar 

  62. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43(8):487–514. doi:10.2165/00003088-200443080-00001.

    Article  CAS  PubMed  Google Scholar 

  63. Bode CJ, Jin H, Rytting E, Silverstein PS, Young AM, Audus KL. In vitro models for studying trophoblast transcellular transport. Methods Mol Med. 2006;122:225–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Cerneus DP, van der Ende A. Apical and basolateral transferrin receptors in polarized BeWo cells recycle through separate endosomes. J Cell Biol. 1991;114(6):1149–58.

    Article  CAS  PubMed  Google Scholar 

  65. Li H, Rietjens IM, Louisse J, Blok M, Wang X, Snijders L, van Ravenzwaay B. Use of the ES-D3 cell differentiation assay, combined with the BeWo transport model, to predict relative in vivo developmental toxicity of antifungal compounds. Toxicol In Vitro. 2015;29(2):320–8. doi:10.1016/j.tiv.2014.11.012.

    Article  CAS  PubMed  Google Scholar 

  66. Castellucci M, Scheper M, Scheffen I, Celona A, Kaufmann P. The development of the human placental villous tree. Anat Embryol. 1990;181(2):117–28.

    Article  CAS  PubMed  Google Scholar 

  67. Larsen Jr JW, Greendale K. ACOG Technical Bulletin Number 84—February 1985: teratology. Teratology. 1985;32(3):493–6. doi:10.1002/tera.1420320319.

    Article  PubMed  Google Scholar 

  68. Nau H. Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol. 2001;45(5):S183–7. doi:10.1067/mjd.2001.113720.

    Article  CAS  PubMed  Google Scholar 

  69. Krtolica A, Ilic D, Genbacev O, Miller RK. Human embryonic stem cells as a model for embryotoxicity screening. Regen Med. 2009;4(3):449–59. doi:10.2217/rme.09.13.

    Article  CAS  PubMed  Google Scholar 

  70. Jensen J, Hyllner J, Bjorquist P. Human embryonic stem cell technologies and drug discovery. J Cell Physiol. 2009;219(3):513–9. doi:10.1002/jcp.21732.

    Article  CAS  PubMed  Google Scholar 

  71. Adler S, Lindqvist J, Uddenberg K, Hyllner J, Strehl R. Testing potential developmental toxicants with a cytotoxicity assay based on human embryonic stem cells. Altern Lab Anim. 2008;36(2):129–40.

    CAS  PubMed  Google Scholar 

  72. Adler S, Pellizzer C, Hareng L, Hartung T, Bremer S. First steps in establishing a developmental toxicity test method based on human embryonic stem cells. Toxicol In Vitro. 2008;22(1):200–11. doi:10.1016/j.tiv.2007.07.013.

    Article  CAS  PubMed  Google Scholar 

  73. Jung EM, Choi YU, Kang HS, Yang H, Hong EJ, An BS, Yang JY, Choi KH, Jeung EB. Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015;35(2):205–18. doi:10.1002/jat.3010.

    Article  CAS  PubMed  Google Scholar 

  74. Kaufman DS, Thomson JA. Human ES cells—haematopoiesis and transplantation strategies. J Anat. 2002;200(Pt 3):243–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Guan K, Furst DO, Wobus AM. Modulation of sarcomere organization during embryonic stem cell-derived cardiomyocyte differentiation. Eur J Cell Biol. 1999;78(11):813–23. doi:10.1016/S0171-9335(99)80032-6.

    Article  CAS  PubMed  Google Scholar 

  76. Laustriat D, Gide J, Peschanski M. Human pluripotent stem cells in drug discovery and predictive toxicology. Biochem Soc Trans. 2010;38(4):1051–7. doi:10.1042/BST0381051.

    Article  CAS  PubMed  Google Scholar 

  77. Trosko JE, Chang CC. Factors to consider in the use of stem cells for pharmaceutic drug development and for chemical safety assessment. Toxicology. 2010;270(1):18–34. doi:10.1016/j.tox.2009.11.019.

    Article  CAS  PubMed  Google Scholar 

  78. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006;7(6):889–908. doi:10.2217/14622416.7.6.889.

    Article  CAS  PubMed  Google Scholar 

  79. Laverty H, Benson C, Cartwright E, Cross M, Garland C, Hammond T, Holloway C, McMahon N, Milligan J, Park B, Pirmohamed M, Pollard C, Radford J, Roome N, Sager P, Singh S, Suter T, Suter W, Trafford A, Volders P, Wallis R, Weaver R, York M, Valentin J. How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br J Clin Pharmacol. 2011;163(4):675–93. doi:10.1111/j.1476-5381.2011.01255.x.

    Article  CAS  Google Scholar 

  80. Burridge PW, Keller G, Gold JD, Wu JC. Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell. 2012;10(1):16–28. doi:10.1016/j.stem.2011.12.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Moretti A, Laugwitz KL, Dorn T, Sinnecker D, Mummery C. Pluripotent stem cell models of human heart disease. Cold Spring Harb Perspect Med. 2013;3(11). doi:10.1101/cshperspect.a014027.

    Google Scholar 

  82. Gupta MK, Illich DJ, Gaarz A, Matzkies M, Nguemo F, Pfannkuche K, Liang H, Classen S, Reppel M, Schultze JL, Hescheler J, Saric T. Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. BMC Dev Biol. 2010;10:98. doi:10.1186/1471-213X-10-98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Liang P, Lan F, Lee AS, Gong T, Sanchez-Freire V, Wang Y, Diecke S, Sallam K, Knowles JW, Wang PJ, Nguyen PK, Bers DM, Robbins RC, Wu JC. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation. 2013;127(16):1677–91. doi:10.1161/CIRCULATIONAHA.113.001883.

    Article  CAS  PubMed  Google Scholar 

  84. Sinnecker D, Laugwitz KL, Moretti A. Induced pluripotent stem cell-derived cardiomyocytes for drug development and toxicity testing. Pharmacol Ther. 2014;143(2):246–52. doi:10.1016/j.pharmthera.2014.03.004.

    Article  CAS  PubMed  Google Scholar 

  85. Guengerich FP. Mechanisms of drug toxicity and relevance to pharmaceutical development. Drug Metab Pharmacokinet. 2011;26(1):3–14.

    Article  CAS  PubMed  Google Scholar 

  86. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474–85. doi:10.1056/NEJMra021844.

    Article  CAS  PubMed  Google Scholar 

  87. Schuster D, Laggner C, Langer T. Why drugs fail—a study on side effects in new chemical entities. Curr Pharm Des. 2005;11(27):3545–59.

    Article  CAS  PubMed  Google Scholar 

  88. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis. 2002;22(2):137–44. doi:10.1055/s-2002-30100.

    Article  CAS  PubMed  Google Scholar 

  89. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. 2000;32(1):56–67. doi:10.1006/rtph.2000.1399.

    Article  CAS  PubMed  Google Scholar 

  90. Du Y, Wang J, Jia J, Song N, Xiang C, Xu J, Hou Z, Su X, Liu B, Jiang T, Zhao D, Sun Y, Shu J, Guo Q, Yin M, Sun D, Lu S, Shi Y, Deng H. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell. 2014;14(3):394–403. doi:10.1016/j.stem.2014.01.008.

    Article  CAS  PubMed  Google Scholar 

  91. Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell. 2010;18(2):175–89. doi:10.1016/j.devcel.2010.01.011.

    Article  CAS  PubMed  Google Scholar 

  92. Ogawa S, Surapisitchat J, Virtanen C, Ogawa M, Niapour M, Sugamori KS, Wang S, Tamblyn L, Guillemette C, Hoffmann E, Zhao B, Strom S, Laposa RR, Tyndale RF, Grant DM, Keller G. Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes. Development. 2013;140(15):3285–96. doi:10.1242/dev.090266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Baxter M, Withey S, Harrison S, Segeritz CP, Zhang F, Atkinson-Dell R, Rowe C, Gerrard DT, Sison-Young R, Jenkins R, Henry J, Berry AA, Mohamet L, Best M, Fenwick SW, Malik H, Kitteringham NR, Goldring CE, Piper Hanley K, Vallier L, Hanley NA. Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. J Hepatol. 2015;62(3):581–9. doi:10.1016/j.jhep.2014.10.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fahad AS. Prevalence of Human Herpesvirus-8 (HHV-8) in untreated patients with early stage Mycosis Fungoides (A retrospective study). Int J Health Sci. 2010;4(2):128–38.

    Google Scholar 

  95. Kulkarni JS, Khanna A. Functional hepatocyte-like cells derived from mouse embryonic stem cells: a novel in vitro hepatotoxicity model for drug screening. Toxicol In Vitro. 2006;20(6):1014–22. doi:10.1016/j.tiv.2005.12.011.

    Article  CAS  PubMed  Google Scholar 

  96. LeCluyse EL, Witek RP, Andersen ME, Powers MJ. Organotypic liver culture models: meeting current challenges in toxicity testing. Crit Rev Toxicol. 2012;42(6):501–48. doi:10.3109/10408444.2012.682115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Santostefano KE, Hamazaki T, Biel NM, Jin S, Umezawa A, Terada N. A practical guide to induced pluripotent stem cell research using patient samples. Lab Invest. 2015;95(1):4–13. doi:10.1038/labinvest.2014.104.

    Article  CAS  PubMed  Google Scholar 

  98. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ. Disease-specific induced pluripotent stem cells. Cell. 2008;134(5):877–86. doi:10.1016/j.cell.2008.07.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, Shah SJ, Ahmed A, Bonow RO, Cleland JG, Cody RJ, Chioncel O, Collins SP, Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, Nodari S, O’Connor C, Pfeffer MA, Pieske B, Pitt B, Rosano G, Sabbah HN, Senni M, Solomon SD, Stockbridge N, Teerlink JR, Georgiopoulou VV, Gheorghiade M. Developing therapies for heart failure with preserved ejection fraction: current state and future directions. JACC Heart Fail. 2014;2(2):97–112. doi:10.1016/j.jchf.2013.10.006.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ebben JD, Zorniak M, Clark PA, Kuo JS. Introduction to induced pluripotent stem cells: advancing the potential for personalized medicine. World Neurosurg. 2011;76(3–4):270–5. doi:10.1016/j.wneu.2010.12.055.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kari G, Rodeck U, Dicker AP. Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharmacol Ther. 2007;82(1):70–80. doi:10.1038/sj.clpt.6100223.

    Article  CAS  PubMed  Google Scholar 

  102. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363(15):1397–409. doi:10.1056/NEJMoa0908679.

    Article  CAS  PubMed  Google Scholar 

  103. Egashira T, Yuasa S, Suzuki T, Aizawa Y, Yamakawa H, Matsuhashi T, Ohno Y, Tohyama S, Okata S, Seki T, Kuroda Y, Yae K, Hashimoto H, Tanaka T, Hattori F, Sato T, Miyoshi S, Takatsuki S, Murata M, Kurokawa J, Furukawa T, Makita N, Aiba T, Shimizu W, Horie M, Kamiya K, Kodama I, Ogawa S, Fukuda K. Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc Res. 2012;95(4):419–29. doi:10.1093/cvr/cvs206.

    Article  CAS  PubMed  Google Scholar 

  104. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel G, Hammerman H, Boulos M, Gepstein L. Modelling the long QT syndrome with induced pluripotent stem cells. Nature. 2011;471(7337):225–9. doi:10.1038/nature09747.

    Article  CAS  PubMed  Google Scholar 

  105. Matsa E, Rajamohan D, Dick E, Young L, Mellor I, Staniforth A, Denning C. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J. 2011;32(8):952–62. doi:10.1093/eurheartj/ehr073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lahti AL, Kujala VJ, Chapman H, Koivisto AP, Pekkanen-Mattila M, Kerkela E, Hyttinen J, Kontula K, Swan H, Conklin BR, Yamanaka S, Silvennoinen O, Aalto-Setala K. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Model Mech. 2012;5(2):220–30. doi:10.1242/dmm.008409.

    Article  CAS  PubMed  Google Scholar 

  107. Davis RP, Casini S, van den Berg CW, Hoekstra M, Remme CA, Dambrot C, Salvatori D, Oostwaard DW, Wilde AA, Bezzina CR, Verkerk AO, Freund C, Mummery CL. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation. 2012;125(25):3079–91. doi:10.1161/CIRCULATIONAHA.111.066092.

    Article  PubMed  Google Scholar 

  108. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471(7337):230–4. doi:10.1038/nature09855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, Rosa AO, Nguemo F, Matzkies M, Dittmann S, Stone SL, Linke M, Zechner U, Beyer V, Hennies HC, Rosenkranz S, Klauke B, Parwani AS, Haverkamp W, Pfitzer G, Farr M, Cleemann L, Morad M, Milting H, Hescheler J, Saric T. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell Physiol Biochem. 2011;28(4):579–92. doi:10.1159/000335753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jung CB, Moretti A, Mederos y Schnitzler M, Iop L, Storch U, Bellin M, Dorn T, Ruppenthal S, Pfeiffer S, Goedel A, Dirschinger RJ, Seyfarth M, Lam JT, Sinnecker D, Gudermann T, Lipp P, Laugwitz KL. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med. 2012;4(3):180–91. doi:10.1002/emmm.201100194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Itzhaki I, Maizels L, Huber I, Gepstein A, Arbel G, Caspi O, Miller L, Belhassen B, Nof E, Glikson M, Gepstein L. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol. 2012;60(11):990–1000. doi:10.1016/j.jacc.2012.02.066.

    Article  CAS  PubMed  Google Scholar 

  112. Novak A, Barad L, Zeevi-Levin N, Shick R, Shtrichman R, Lorber A, Itskovitz-Eldor J, Binah O. Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to beta-adrenergic stimulation. J Cell Mol Med. 2012;16(3):468–82. doi:10.1111/j.1582-4934.2011.01476.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, Navarrete EG, Hu S, Wang L, Lee A, Pavlovic A, Lin S, Chen R, Hajjar RJ, Snyder MP, Dolmetsch RE, Butte MJ, Ashley EA, Longaker MT, Robbins RC, Wu JC. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4(130):130ra147. doi:10.1126/scitranslmed.3003552.

    Article  Google Scholar 

  114. Lan F, Lee AS, Liang P, Sanchez-Freire V, Nguyen PK, Wang L, Han L, Yen M, Wang Y, Sun N, Abilez OJ, Hu S, Ebert AD, Navarrete EG, Simmons CS, Wheeler M, Pruitt B, Lewis R, Yamaguchi Y, Ashley EA, Bers DM, Robbins RC, Longaker MT, Wu JC. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12(1):101–13. doi:10.1016/j.stem.2012.10.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Carvajal-Vergara X, Sevilla A, D’Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature. 2010;465(7299):808–12. doi:10.1038/nature09005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ma D, Wei H, Lu J, Ho S, Zhang G, Sun X, Oh Y, Tan SH, Ng ML, Shim W, Wong P, Liew R. Generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes as a cellular model of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2013;34(15):1122–33. doi:10.1093/eurheartj/ehs226.

    Article  CAS  PubMed  Google Scholar 

  117. Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, Kan NG, Forcales S, Puri PL, Leone TC, Marine JE, Calkins H, Kelly DP, Judge DP, Chen HS. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013;494(7435):105–10. doi:10.1038/nature11799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Caspi O, Huber I, Gepstein A, Arbel G, Maizels L, Boulos M, Gepstein L. Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells. Circ Cardiovasc Genet. 2013;6(6):557–68. doi:10.1161/CIRCGENETICS.113.000188.

    Article  CAS  PubMed  Google Scholar 

  119. Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest. 2010;120(9):3127–36. doi:10.1172/JCI43122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ghodsizadeh A, Taei A, Totonchi M, Seifinejad A, Gourabi H, Pournasr B, Aghdami N, Malekzadeh R, Almadani N, Salekdeh GH, Baharvand H. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev. 2010;6(4):622–32. doi:10.1007/s12015-010-9189-3.

    Article  PubMed  Google Scholar 

  121. Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature. 2012;481(7381):295–305. doi:10.1038/nature10761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant (15182MFDS460) from Ministry of Food and Drug Safety in 2016.

Author information

Authors and Affiliations

  1. Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea

    Hee Young Kang & Eui-Bae Jeung

Authors
  1. Hee Young Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eui-Bae Jeung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eui-Bae Jeung .

Editor information

Editors and Affiliations

  1. Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar

    Essam M. Abdelalim

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Kang, H.Y., Jeung, EB. (2016). Stem Cells for Drug Screening. In: Abdelalim, E. (eds) Recent Advances in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-33270-3_2

Download citation

Publish with us

Policies and ethics

Search

Navigation