Abstract
Embryonic stem (ES) cells may acquire genetic and epigenetic changes upon prolonged passage in culture, which can confer on them more robust growth characteristics. The genetic changes are often manifest cytogenetically as nonrandom gains of chromosomal regions that are also typically amplified in embryonal carcinoma (EC) cells, the malignant counterpart of ES cells. Although this raises some concerns for the future use of ES or induced pluripotent stem (iPS) cells in regenerative medicine, or in vitro screening applications, these concerns remain largely hypothetical. It may be that potential problems can be substantially mitigated when we understand more about the underlying causes and mechanisms of culture adaptation. At the same time, this phenomenon also provides a tool that can help dissect the mechanisms controlling stem cell behavior, while potentially providing more robust cells for use in some applications.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adewumi O, Aflatoonian B, Ahrlund-Richter L, Amit M, Andrews PW, Beighton G, Bello PA, Benvenisty N, Berry LS, Bevan S et al (2007) Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25:803–816
Akopian V, Andrews PW, Beil S, Benvenisty N, Brehm J, Christie M, Ford A, Fox V, Gokhale PJ, Healy L et al (2010) Comparison of defined culture systems for feeder cell free propagation of human embryonic stem cells. In Vitro Cell Dev Biol Anim 46:247–258
Allegrucci C, Young LE (2007) Differences between human embryonic stem cell lines. Hum Reprod Update 13:103–120
Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA (2000) Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 227:271–278
Andrews PW, Bronson DL, Benham F, Strickland S, Knowles BB (1980) A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int J Cancer 26:269–280
Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33:1526–1530
Astuti D, Latif F, Wagner K, Gentle D, Cooper WN, Catchpoole D, Grundy R, Ferguson-Smith AC, Maher ER (2005) Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms’ tumour. Br J Cancer 92:1574–1580
Baker DE, Harrison NJ, Maltby E, Smith K, Moore HD, Shaw PJ, Heath PR, Holden H, Andrews PW (2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol 25:207–215
Berstine EG, Hooper ML, Grandchamp S, Ephrussi B (1973) Alkaline phosphatase activity in mouse teratoma. Proc Natl Acad Sci USA 70:3899–3903
Blum B, Benvenisty N (2009) The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8:3822–3830
Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N (2009) The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol 27:281–287
Brimble SN, Zeng X, Weiler DA, Luo Y, Liu Y, Lyons IG, Freed WJ, Robins AJ, Rao MS, Schulz TC (2004) Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines derived prior to August 9, 2001. Stem Cells Dev 13:585–597
Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200
Caisander G, Park H, Frej K, Lindqvist J, Bergh C, Lundin K, Hanson C (2006) Chromosomal integrity maintained in five human embryonic stem cell lines after prolonged in vitro culture. Chromosome Res 14:131–137
Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M, Vrana J, Jones K, Grotewold L, Smith A (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450:1230–1234
Cowan CA, Klimanskaya I, McMahon J, Atienza J, Witmyer J, Zucker JP, Wang S, Morton CC, McMahon AP, Powers D, Melton DA (2004) Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med 350:1353–1356
Darr H, Mayshar Y, Benvenisty N (2006) Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development 133:1193–1201
Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci USA 100:3547–3549
Dick JE (2008) Stem cell concepts renew cancer research. Blood 112:4793–4807
Draper JS, Moore HD, Ruban LN, Gokhale PJ, Andrews PW (2004a) Culture and characterization of human embryonic stem cells. Stem Cells Dev 13:325–336
Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA, Andrews PW (2004b) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol 22:53–54
Eggan K, Rode A, Jentsch I, Samuel C, Hennek T, Tintrup H, Zevnik B, Erwin J, Loring J, Jackson-Grusby L et al (2002) Male and female mice derived from the same embryonic stem cell clone by tetraploid embryo complementation. Nat Biotechnol 20:455–459
Enver T, Soneji S, Joshi C, Brown J, Iborra F, Orntoft T, Thykjaer T, Maltby E, Smith K, Dawud RA et al (2005) Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet 14:3129–3140
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156
Fox V, Gokhale PJ, Walsh JR, Matin M, Jones M, Andrews PW (2008) Cell-cell signaling through NOTCH regulates human embryonic stem cell proliferation. Stem Cells 26:715–723
Guo J, Jauch A, Heidi HG, Schoell B, Erz D, Schrank M, Janssen JW (2005) Multicolor karyotype analyses of mouse embryonic stem cells. In Vitro Cell Dev Biol Anim 41:278–283
Harris H (2004) Tumour suppression: putting on the brakes. Nature 427:201
Harrison NJ, Barnes J, Jones M, Baker D, Gokhale PJ, Andrews PW (2009) CD30 expression reveals that culture adaptation of human embryonic stem cells can occur through differing routes. Stem Cells 27:1057–1065
Herszfeld D, Wolvetang E, Langton-Bunker E, Chung TL, Filipczyk AA, Houssami S, Jamshidi P, Koh K, Laslett AL, Michalska A et al (2006) CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells. Nat Biotechnol 24:351–357
Holliday R (1989) Chromosome error propagation and cancer. Trends Genet 5:42–45
Inzunza J, Sahlen S, Holmberg K, Stromberg AM, Teerijoki H, Blennow E, Hovatta O, Malmgren H (2004) Comparative genomic hybridization and karyotyping of human embryonic stem cells reveals the occurrence of an isodicentric X chromosome after long-term cultivation. Mol Hum Reprod 10:461–466
Kleinsmith LJ, Pierce GB Jr (1964) Multipotentiality of single embryonal carcinoma cells. Cancer Res 24:1544–1551
Lefort N, Feyeux M, Bas C, Feraud O, Bennaceur-Griscelli A, Tachdjian G, Peschanski M, Perrier AL (2008) Human embryonic stem cells reveal recurrent genomic instability at 20q11.21. Nat Biotechnol 26:1364–1366
Liu X, Wu H, Loring J, Hormuzdi S, Disteche CM, Bornstein P, Jaenisch R (1997) Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission. Dev Dyn 209:85–91
Longo L, Bygrave A, Grosveld FG, Pandolfi PP (1997) The chromosome make-up of mouse embryonic stem cells is predictive of somatic and germ cell chimaerism. Transgenic Res 6:321–328
Ludwig TE, Levenstein ME, Jones JM, Berggren WT, Mitchen ER, Frane JL, Crandall LJ, Daigh CA, Conard KR, Piekarczyk MS et al (2006) Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol 24:185–187
Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638
Martin GR, Evans MJ (1975) Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc Natl Acad Sci USA 72:1441–1445
Mitalipova MM, Rao RR, Hoyer DM, Johnson JA, Meisner LF, Jones KL, Dalton S, Stice SL (2005) Preserving the genetic integrity of human embryonic stem cells. Nat Biotechnol 23:19–20
Mostofi FK, Sesterhenn IA (1985) Pathology of germ cell tumors of testes. Prog Clin Biol Res 203:1–34
Narva E, Autio R, Rahkonen N, Kong L, Harrison N, Kitsberg D, Borghese L, Itskovitz-Eldor J, Rasool O, Dvorak P et al (2010) High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nat Biotechnol 28:371–377
Olariu V, Harrison NJ, Coca D, Gokhale PJ, Baker D, Billings S, Kadirkamanathan V, Andrews PW (2010) Modeling the evolution of culture-adapted human embryonic stem cells. Stem Cell Res 4:50–56
Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR, Melton DA (2008) Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26:313–315
Petersson H, Mitelman F (1985) Nonrandom de novo chromosome aberrations in human lymphocytes and amniotic cells. Hereditas 102:33–38
Pierce GB Jr, Dixon FJ Jr, Verney EL (1960) Teratocarcinogenic and tissue-forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest 9:583–602
Rugg-Gunn PJ, Ferguson-Smith AC, Pedersen RA (2005) Epigenetic status of human embryonic stem cells. Nat Genet 37:585–587
Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349
Silva SS, Rowntree RK, Mekhoubad S, Lee JT (2008) X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. Proc Natl Acad Sci USA 105:4820–4825
Silver LM, Martin GR, Strickland S (1983) Teratocarcinoma stem cells. Cold Spring Harbour Laboratory, New York
Skotheim RI, Autio R, Lind GE, Kraggerud SM, Andrews PW, Monni O, Kallioniemi O, Lothe RA (2006) Novel genomic aberrations in testicular germ cell tumors by array-CGH, and associated gene expression changes. Cell Oncol 28:315–326
Spits C, Mateizel I, Geens M, Mertzanidou A, Staessen C, Vandeskelde Y, Van der Elst J, Liebaers I, Sermon K (2008) Recurrent chromosomal abnormalities in human embryonic stem cells. Nat Biotechnol 26:1361–1363
Temple IK, Shrubb V, Lever M, Bullman H, Mackay DJ (2007) Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J Med Genet 44:637–640
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147
Till JE, McCulloch EA, Siminovitch L (1964) A Stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proc Natl Acad Sci USA 51:29–36
Wang N, Trend B, Bronson DL, Fraley EE (1980) Nonrandom abnormalities in chromosome 1 in human testicular cancers. Cancer Res 40:796–802
Werbowetski-Ogilvie TE, Bosse M, Stewart M, Schnerch A, Ramos-Mejia V, Rouleau A, Wynder T, Smith MJ, Dingwall S, Carter T et al (2009) Characterization of human embryonic stem cells with features of neoplastic progression. Nat Biotechnol 27:91–97
Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523
Acknowledgments
This work was supported in part by grants from the MRC and from the ESTOOLS consortium, a Sixth Framework Integrated Projected of the European Commission.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Harrison, N.J., Baker, D., Andrews, P.W. (2011). Culture Adaptation of Pluripotent Stem Cells: Challenges and Opportunities. In: Ainscough, J., Yamanaka, S., Tada, T. (eds) Nuclear Reprogramming and Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-225-0_19
Download citation
DOI: https://doi.org/10.1007/978-1-61779-225-0_19
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61779-224-3
Online ISBN: 978-1-61779-225-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)