Skip to main content
SpringerLink
Log in

Embryonic Stem Cells as a Tool for Drug Screening and Toxicity Testing

  • Chapter
  • First Online:
Stem Cell Engineering

  • 1150 Accesses

Abstract

Embryonic stem cells (ESCs) are recognized by the general public mainly as a possible source of cellular replacement therapy and transplantation. However, the usefulness of ESCs and ESC-derived tissue cell types for cell-based in vitro test systems in drug screening and toxicity was already recognized early after the discovery of ESCs in the late 1980s.

In the present chapter, the employment of ESCs in cell-based test systems is described in the light of state-of-the-art methods in the field of drug discovery, and the advantages and disadvantages of the applications are discussed. The possible use of ESCs in the drug development process is illustrated by three examples: (1) the use of ESCs for basic research in early developmental biology, (2) the embryonic stem cell test for embryotoxicity, and (3) the use of ESC-derived cardiomyocytes for detection of cardiac toxicity. Potential applications of human ESCs, induced pluripotent stem cells (IPS cells), and personalized medicine are described in the last part.

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

Similar content being viewed by others

Notes

  1. 1.

    It has to be kept in mind that the results of in vivo toxicity have to be linked to other data, like route of exposure, environmental concentrations, and the mode of action of a compound, to correctly predict the risk for human beings.

  2. 2.

    Schardein described in his book Chemically Induced Birth Defects the effect of the well-known teratogen thalidomide on different strains of laboratory animals: see Schardein [105].

  3. 3.

    From the author’s own experience, the generation of a subclone of the cell line T84 was achieved within 3 months (starting from the same material) only by (a) different passaging intervals and (b) not ensuring that all cells are removed from the plates after trypsinization for passaging.

  4. 4.

    Mouse ESCs maintained in culture for long periods can still generate any tissue when they are reintroduced into an embryo to generate a chimeric animal. Not shown for human ESCs.

  5. 5.

    ESCs are most of the time in the S phase of the cell cycle, during which they synthesize DNA. Unlike differentiated somatic cells, ESCs do not require any external stimulus to initiate DNA replication.

  6. 6.

    One reason for this may be the relatively low number of compounds tested in the validation study. It seems to be necessary to increase these numbers in order to judge for the suitability of the test not only within the drug development process but also for additional applications, like the testing of chemicals within the REACh approach of the European Union [106]. At the moment, seven additional compounds are tested with the EST within the ReProTect consortium, but results are not published yet.

References

  1. Caldwell GW, Ritchie DM, Masucci JA, Hageman W, Yan Z. The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery. Curr Top Med Chem. 2001; 1:353–366.

    Article  Google Scholar 

  2. The Academy of Medical Sciences. Safer medicines report. Pre-clinical toxicology working group report; 2005. http://www.acmedsci.ac.uk/p103.html

  3. Lindsay MA. Finding new drug targets in the 21st century. Drug Discov Today. 2005; 10:1683–1687.

    Article  Google Scholar 

  4. Guttendorf RJ. The emerging role of A.D.M.E. in optimizing drug discovery and design. http://www.netsci.org/Science/Special/feature06.html

  5. Brent RL. Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents). Pediatrics. 2004; 113:984–995.

    Google Scholar 

  6. Guerassimov A, Hoshino Y, Takubo Y, Turcotte A, Yamamoto M, Ghezzo H, Triantafillopoulos A, Whittaker K, Hoidal JR, Cosio MG. The development of emphysema in cigarette smoke-exposed mice is strain dependent. Am J Respir Crit Care Med. 2004; 170:974–980.

    Article  Google Scholar 

  7. Pedersen F, de Bruijn J, Munn S, van Leeuwen K. Assessment of additional testing needs under REACH. Ispra: Publication of the European Commission, Directorate General JRC, Joint Research Centre, Institute for Health and Consumer Protection; 2003.

    Google Scholar 

  8. Skrzypiec-Spring M, Grotthus B, Szelag A, Schulz R. Isolated heart perfusion according to Langendorff—still viable in the new millennium. J Pharmacol Toxicol Methods. 2007; 55:113–126.

    Article  Google Scholar 

  9. van de Kerkhof EG, de Graaf IA, Groothuis GM. In vitro methods to study intestinal drug metabolism. Curr Drug Metab. 2007; 8:658–675.

    Article  Google Scholar 

  10. Haney SA, LaPan P, Pan J, Zhang J. High-content screening moves to the front of the line. Drug Discov Today. 2006; 11:889–894.

    Article  Google Scholar 

  11. Park JK, Kim BH, Han YS, Park IK. The effect of telomerase expression on the escape from M2 crisis in virus-transformed human retinal pigment epithelial cells. Exp Mol Med. 2002; 34:107–113.

    Article  Google Scholar 

  12. Poste G, Greig R. On the genesis and regulation of cellular heterogeneity in malignant tumors. Invasion Metastasis. 1982; 2:137–176.

    Google Scholar 

  13. MacLeod RAF, Nagel S, Scherr M, Schneider B, Dirks WG, Uphoff CC, Quentmeier H, Drexler HG. Human leukemia and lymphoma cell lines as models and resources. Curr Med Chem. 2008; 15:339–359.

    Article  Google Scholar 

  14. Sachinidis A, Fleischmann BK, Kolossov E, Wartenberg M, Sauer H, Hescheler J. Cardiac specific differentiation of mouse embryonic stem cells. Cardiovasc Res. 2003; 58:278–291.

    Article  Google Scholar 

  15. Dang L, Tropepe V. Neural induction and neural stem cell development. Regen Med. 2006; 1:635–652.

    Article  Google Scholar 

  16. Spence JR, Wells JM. Translational embryology: using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells. Dev Dyn. 2007; 236:3218–3227.

    Article  Google Scholar 

  17. Valtieri M, Sorrentino A. The mesenchymal stromal cell contribution to homeostasis. J Cell Physiol. 2008; 217:296–300.

    Article  Google Scholar 

  18. Evans M, Kaufman M. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981; 292:154–156.

    Article  Google Scholar 

  19. Martin G. Isolation of a pluri-potent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981; 78(12):7634–7638.

    Article  Google Scholar 

  20. Bradley A, Evans M, Kaufman MH, Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984; 309:255–256.

    Article  Google Scholar 

  21. Boyer LA, Mathur D, Jaenisch R. Molecular control of pluripotency. Curr Opin Genet Dev. 2006; 16(5):455–462.

    Article  Google Scholar 

  22. Smith AG. Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol. 2001; 17:435–462.

    Article  Google Scholar 

  23. Mueller FJ, KostkaKostka D, Laurent L, Ulitsky I, Williams R, Lu C, Rao MS, Shamir R, Schwartz PH, Schmidt NO, Loring JF. Regulatory networks define phenotypic classes of human stem cell lines. Nature. 2008; 455:401–405.

    Article  Google Scholar 

  24. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282:1145–1147.

    Article  Google Scholar 

  25. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, Hearn JP. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA. 1995; 92:7844–7848.

    Article  Google Scholar 

  26. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Hearn JP. Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod. 1996; 55:254–259.

    Article  Google Scholar 

  27. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988; 336:684–687.

    Article  Google Scholar 

  28. Ying QL, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustained embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003; 115:281–292.

    Article  Google Scholar 

  29. Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development. 2005; 132:885–896.

    Article  Google Scholar 

  30. Hyslop LA, Armstrong L, Stojkovic M, Lako M. Human embryonic stem cells: biology and clinical implications. Expert Rev Mol Med. 2005; 7:1–21.

    Article  Google Scholar 

  31. Dahéron L, Optiz SL, Zaehres H, Lensch MW, Andrews PW, Itskovitz-Eldor J, Daley GQ. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004; 22:770–778.

    Article  Google Scholar 

  32. Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, Rose-John S, Hayek A. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells. 2004; 22:522–530.

    Article  Google Scholar 

  33. Pera MF, Andrade J, Houssami S, Reubinoff B, Trounson A, Stanley EG, Ward-van Oostwaard D, Mummery C. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci. 2004; 117:1269–1280.

    Article  Google Scholar 

  34. Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol. 2002; 20:1261–1264.

    Article  Google Scholar 

  35. Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol. 2000; 227:271–278.

    Article  Google Scholar 

  36. Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD, Carpenter MK. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol. 2001; 19:971–974.

    Article  Google Scholar 

  37. Amit M, Shariki K, Margulets V, Itskovitz-Eldor J. Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod. 2004; 70:837–845.

    Article  Google Scholar 

  38. Ludwig TE, Levenstein ME, Jones JM, Berggren WT, Mitchen ER, Frane JL, Crandall LJ, Daigh CA, Conard KR, Piekarczyk MS, Llanas RA, Thomson JA. Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol. 2006; 24:185–187.

    Article  Google Scholar 

  39. Lu J, Hou R, Booth CJ, Yang SH, Snyder M. Defined culture conditions of human embryonic stem cells. Proc Natl Acad Sci USA. 2006; 103:5688–5693.

    Article  Google Scholar 

  40. Wobus AM, Hescheler J. Development of an in vitro cardiomyocytes cell model for embryotoxicological and pharmacological studies. ALTEX. 1992; 9:29–42.

    Google Scholar 

  41. Davila JC, Cezar GG, Thiede M, Strom S, Miki T, Trosko J. Use and application of stem cells in toxicology. Toxicol Sci. 2004; 79:214–223.

    Article  Google Scholar 

  42. McNeish J. Embryonic stem cells in drug discovery. Nat Rev Drug Discov. 2004; 3:70–80.

    Article  Google Scholar 

  43. Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF III, Boiani M, Schöler HR. Derivation of oocytes from mouse embryonic stem cells. Science. 2003; 300:1251–1256.

    Article  Google Scholar 

  44. Geijsen N, Horoschak M, Kim K, Gribnau J, Eggan K, Daley GQ. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature. 2003; 427: 148–154.

    Article  Google Scholar 

  45. Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development. 1998; 125:1747–1757.

    Google Scholar 

  46. Ng ES, Azzola L, Sourris K, Robb L, Stanley EG, Elefanty AG. The primitive streak gene Mixl1 is required for efficient haematopoiesis and BMP4-induced ventral mesoderm patterning in differentiating ES cells. Development. 2005; 132:873–884.

    Article  Google Scholar 

  47. Spielmann H, Pohl I, Döring B, Liebsch M, Moldenhauer F. The embryonic stem cell test, an in vitro embryotoxicity test using permanent mouse cell lines: 3T3 fibroblasts and embryonic stem cells. In Vitro Toxicol. 1997; 10:119–127.

    Google Scholar 

  48. 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. 1985; 87:27–45.

    Google Scholar 

  49. Genschow E, Spielmann H, Scholz G, Seiler A, Brown N, Piersma A, Brady M, Clemann N, Huuskonen H, Paillard F, Bremer S, Becker K. The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. European Centre for the Validation of Alternative Methods. ATLA. 2002; 30: 151–176.

    Google Scholar 

  50. 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; 165:203–211.

    Article  Google Scholar 

  51. Paparella M, Kolossov E, Fleischmann BK, Hescheler J, Bremer S. The use of quantitative image analysis in the assessment of in vitro embryotoxicity endpoints based on a novel embryonic stem cell clone with endoderm-related GFP expression. Toxicol In Vitro. 2002; 16:589–597.

    Article  Google Scholar 

  52. Schwengberg S, Bohlen H, Kleinsasser N, Kehe K, Seiss M, Walther UI, Hickel R, Reichl FX. In vitro embryotoxicity assessment with dental restorative materials. J Dent. 2005; 33:49–55.

    Article  Google Scholar 

  53. Pellizzer C, Adler S, Corvi R, Hartung T, Bremer S. Monitoring of teratogenic effects in vitro by analysing a selected gene expression pattern. Toxicol In Vitro. 2004; 18:325–335.

    Article  Google Scholar 

  54. zur Nieden NI, Kempka G, Ahr HJ. Molecular multiple endpoint embryonic stem cell test—a possible approach to test for the teratogenic potential of compounds. Toxicol Appl Pharmacol. 2004; 194:257–269.

    Article  Google Scholar 

  55. Hareng L, Pellizzer C, Bremer S, Schwarz M, Hartung T. The integrated project ReProTect: a novel approach in reproductive toxicity hazard assessment. Reprod Toxicol. 2005; 20: 441–452.

    Article  Google Scholar 

  56. Brown NA. Selection of test chemicals for the ECVAM international validation study on in vitro embryotoxicity tests. European Centre for the Validation of Alternative Methods. ATLA. 2002; 30:177–198.

    Google Scholar 

  57. 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. ATLA. 2004; 32:209–244.

    Google Scholar 

  58. Bremer S, Hartung T. The use of embryonic stem cells for regulatory developmental toxicity testing in vitro—the current status of test development. Curr Pharm Des. 2004; 10: 2733–2747.

    Article  Google Scholar 

  59. 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. 2008; 83:104–111.

    Article  Google Scholar 

  60. Castellucci M, Scheper M, Scheffen I, Celona A, Kaufmann P. The development of the human placental villous tree. Anat Embryol (Berlin) 1990; 18:117–128.

    Google Scholar 

  61. Luckett WP. The development of primordial and definitive amniotic cavities in early Rhesus monkey and human embryos. Am J Anat. 1975; 144:149–167.

    Article  Google Scholar 

  62. Luckett WP. Origin and differentiation of the yolk sac and extra-embryonic mesoderm in presomite human and rhesus monkey embryos. Am J Anat. 1978; 152:59–97.

    Article  Google Scholar 

  63. Gussak I, Litwin J, Kleiman R, Grisanti S, Morganroth J. Drug-induced cardiac toxicity: emphasising the role of electrocardiography in clinical research and drug development. J Electrocardiol. 2004; 37:19–24.

    Article  Google Scholar 

  64. Lawrence CL, Pollard CE, Hammond TG, Valentin JP. Nonclinical proarrhythmia models: predicting Torsades de Pointes. J Pharmacol Toxicol Methods. 2005; 52:46–59.

    Article  Google Scholar 

  65. Moe GW, Marin-Garcia J, Konig A, Goldenthal M, Lu X, Feng Q. In vivo TNF-alpha inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure. Am J Physiol Heart Circ Physiol. 2004; 287:1813–1820.

    Article  Google Scholar 

  66. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res. 1997; 81:627–635.

    Article  Google Scholar 

  67. Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res. 1998; 83:969–979.

    Article  Google Scholar 

  68. Valentin JP, Hoffmann P, De Clerck F, Hammond TG, Hondeghem L. Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. J Pharmacol Toxicol Methods. 2004; 49:171–181.

    Article  Google Scholar 

  69. Testai L, Breschi MC, Martinotti E, Calderone V. QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II. J Appl Toxicol. 2007; 27:270–275.

    Article  Google Scholar 

  70. Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med. 2002; 27:545–555.

    Google Scholar 

  71. Arrigoni C, Crivori P. Assessment of QT liabilities in drug development. Cell Biol Toxicol. 2007; 23:1–13.

    Article  Google Scholar 

  72. Davie C, Pierre-Valentin J, Pollard C, Standen N, Mitcheson J, Alexander P, Thong B. Comparative pharmacology of guinea pig cardiac myocyte and cloned hERG (I(Kr)) channel. J Cardiovasc Electrophysiol. 2004; 15:1302–1309.

    Article  Google Scholar 

  73. White SM, Constantin PE, Claycomb WC. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am J Physiol Heart Circ Physiol. 2004; 286:823–829.

    Article  Google Scholar 

  74. Kimes BW, Brandt BL. Properties of a clonal muscle cell line from rat heart. Exp Cell Res. 1976; 98:367–381.

    Article  Google Scholar 

  75. Hescheler J, Meyer R, Plant S, Krautwurst D, Rosenthal W, Schultz G. Morphological, biochemical, and electrophysiological characterization of a clonal cell (H9c2) line from rat heart. Circ Res. 1991; 69:1476–1486.

    Article  Google Scholar 

  76. Li K, Sung RY, Huang WZ, Yang M, Pong NH, Lee SM, Chan WY, Zhao H, To MY, Fok TF, Li CK, Wong YO, Ng PC. Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation. 2006; 113:2211–2220.

    Article  Google Scholar 

  77. Menna P, Salvatorelli E, Minotti G. Doxorubicin degradation in cardiomyocytes. J Pharmacol Exp Ther. 2007; 322:408–419.

    Article  Google Scholar 

  78. Hofgaard JP, Sigurdardottir KS, Treiman M. Protection by 6-aminonicotinamide against oxidative stress in cardiac cells. Pharmacol Res. 2006; 54:303–310.

    Article  Google Scholar 

  79. Priest BT, Swensen AM, McManus OB. Automated electrophysiology in drug discovery. Curr Pharm Des. 2007; 13:2325–2337.

    Article  Google Scholar 

  80. Pehl U, Leisgen C, Gampe K, Guenther E. Automated higher-throughput compound screening on ion channel targets based on the Xenopus laevis oocyte expression system. Assay Drug Dev Technol. 2004; 2:515–524.

    Google Scholar 

  81. Wobus AM, Wallukat G, Hescheler J. Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers. Differentiation. 1991; 48:173–182.

    Article  Google Scholar 

  82. Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren JM, Sasse P, Rubenchik O, Fries JW, Wenzel D, Geisen C, Xia Y, Lu Z, Duan Y, Kettenhofen R, Jovinge S, Bloch W, Bohlen H, Welz A, Hescheler J, Jacobsen SE, Fleischmann BK. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med. 2006; 203:2315–2327.

    Article  Google Scholar 

  83. Kettenhofen R, Bohlen H. Preclinical assessment of cardiac toxicity. Drug Discov Today. 2008; 13:702–707.

    Article  Google Scholar 

  84. Kolossov E, Lu Z, Drobinskaya I, Gassanov N, Duan Y, Sauer H, Manzke O, Bloch W, Bohlen H, Hescheler J, Fleischmann BK. Identification and characterization of embryonic stem cell-derived pacemaker and atrial cardiomyocytes. FASEB J. 2005; 19:577–579.

    Google Scholar 

  85. Hescheler J, Halbach M, Egert U, Lu ZJ, Bohlen H, Fleischmann BK, Reppel M. Determination of electrical properties of ES cell-derived cardiomyocytes using MEAs. J Electrocardiol. 2004; 37:110–116.

    Article  Google Scholar 

  86. Schwengberg S, Kettenhofen R, Clarke E, Bohlen H. Use of embryonic stem cell derived cardiomyocytes for determination of cardiac cytotoxicity. Safety Pharmacology Society Annual Meeting, Madison, WI; 2008.

    Google Scholar 

  87. Abassi Y, Bohlen H. The application of cell-based impedance technology in drug discovery. SBS Symposium Europe, Dresden, Germany; 2008.

    Google Scholar 

  88. Thedinga E, Ullrich A, Drechsler S, Niendorf R, Kob A, Runge D, Keuer A, Freund I, Lehmann M, Ehret R. In vitro system for the prediction of hepatotoxic effects in primary hepatocytes. ALTEX. 2007; 24:22–34.

    Google Scholar 

  89. Thomson H. Bioprocessing of embryonic stem cells for drug discovery. Trends Biotechnol. 2007; 25:224–230.

    Article  Google Scholar 

  90. Christie VB, Barnard JH, Batsanov AS, Bridgens CE, Cartmell EB, Collings JC, Maltman DJ, Redfern CPF, Marder TB, Przyborski S, Whiting A. Synthesis and evaluation of synthetic retinoid derivatives as inducers of stem cell differentiation. Org Biomol Chem. 2008; 19:3497–3507.

    Article  Google Scholar 

  91. Aden DP, Fogel A, Plotkin S, Damjanov I, Knowles BB. Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature. 1979; 282: 615–616.

    Article  Google Scholar 

  92. Zeilinger K, Holland G, Sauer IM, Efimova E, Kardassis D, Obermayer N, Liu M, Neuhaus P, Gerlach JC. Time course of primary liver cell reorganization in three-dimensional high-density bioreactors for extracorporeal liver support: an immunohistochemical and ultrastructural study. Tissue Eng. 2004; 10:1113–1124.

    Google Scholar 

  93. Verlinsky Y, Strelchenko N, Kukharenko V, Rechitsky S, Verlinsky O, Galat V, Kuliev A. Human embryonic stem cell lines with genetic disorders. Reprod Biomed Online. 2005; 10:105–110.

    Article  Google Scholar 

  94. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126:663–676.

    Article  Google Scholar 

  95. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007; 448:318–324.

    Article  Google Scholar 

  96. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007; 1:55–70.

    Article  Google Scholar 

  97. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318:1917–1920.

    Article  Google Scholar 

  98. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 31: 861–872.

    Article  Google Scholar 

  99. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008; 322:949–953.

    Article  Google Scholar 

  100. Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science. 2007; 21:1920–1923.

    Article  Google Scholar 

  101. Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K. A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell. 2008; 3:340–345.

    Article  Google Scholar 

  102. Park IH, Lerou PH, Zhao R, Huo H, Daley GQ. Generation of human-induced pluripotent stem cells. Nat Protoc. 2008; 3:1180–1186.

    Article  Google Scholar 

  103. Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008; 26:808–816.

    Article  Google Scholar 

  104. Hütter G, Nowak D, Mossner M, Ganepola S, Allers K, Schneider T, Hofmann J, Blau IW, Hofmann WK, Thiel E. Treatment of HIV-1 infection by allogeneic CCR5-delta32/delta32 stem cell transplantation: a promising approach. Poster, 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 3–6, 2008.

    Google Scholar 

  105. Schardein JL Chemically induced birth defects. 3rd edition New York NY: Marcel Dekker; 2000.

    Google Scholar 

  106. Van der Jagt K, Munn S, Tørsløv J, de Bruijn J. Alternative approaches can reduce the use of test animals under REACH. Addendum to the report “Assessment of additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives”. JRC Report EUR 21405 EN, Ispra, Italy; 2004, 25pp.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. IZKF “BIOMAT.”, RWTH, Aachen, Germany

    Bernd Denecke

  2. Axiogenesis AG, Köln, Germany

    Silke Schwengberg

Authors
  1. Bernd Denecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silke Schwengberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Denecke .

Editor information

Editors and Affiliations

  1. FH Aachen, Standort Jülich, Ginsterweg 1, Jülich, 52428, Germany

    Gerhard M. Artmann

  2. Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College London, London, SE11UL, United Kingdom

    Stephen Minger

  3. Inst. Neurophysiologie, Universitätsklinikum Köln, Robert-Koch-Str. 39, Köln, 50931, Germany

    Jürgen Hescheler

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Denecke, B., Schwengberg, S. (2011). Embryonic Stem Cells as a Tool for Drug Screening and Toxicity Testing. In: Artmann, G., Minger, S., Hescheler, J. (eds) Stem Cell Engineering. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11865-4_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-11865-4_22

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-11864-7

  • Online ISBN: 978-3-642-11865-4

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics

Search

Navigation