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Lessons from human teratomas to guide development of safe stem cell therapies

Nature Biotechnology volume 30, pages 849–857 (2012)Cite this article

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A Corrigendum to this article was published on 10 June 2013

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Abstract

The potential for the formation of teratomas or other neoplasms is a major safety roadblock to clinical application of pluripotent stem cell therapies. Preclinical assessment of the risk of tumor formation in this context poses considerable scientific and regulatory challenges, especially because animal xenograft models may not properly reflect the long-term tumorigenic potential of human cells. A better understanding of the biology of spontaneously occurring teratomas and related tumors in humans can help to guide efforts to assess and minimize the potential hazards of embryonic stem cell or induced pluripotent stem cell therapeutics. Here we review the features of teratomas derived experimentally from human pluripotent stem cells and argue that they most closely resemble spontaneous benign teratomas that occur early in both mouse and human life. The natural history and pathology of these spontaneously occurring teratomas provide important clues for preclinical safety assessment and patient monitoring in trials of stem cell therapies.

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Figure 1: Teratoma from hES cells showing varying degrees of maturation.
Figure 2: Genomic imprinting and developmental origin of GCTs.
Figure 3: Histologic features characteristic of malignant progression in human teratomas.

Change history

  • 04 June 2013

    In the version of this article initially published, there were two errors in the discussion of epigenetic marks on page 854. In sentence 4, paragraph 2 of the section “Genetic and epigenetic changes predictive of malignancy,” dimethylated and trimethylated H3K9 were said incorrectly to be “polycomb” marks. “Polycomb” has been deleted from the sentence, and the following two sentences inserted for clarification: “In ES cells these genes are held in a 'transcription ready' state by two marks, a repressive H3K27me mark and an active mark, H3K4me64. Changes in the balance of repressive versus active marks can alter the activity of these genes, hypothetically keeping cells in a proliferative state.” Further down in the paragraph, DNMT3L was described incorrectly as catalytic. The original text, “… related to activation of the de novo methyltransferase DNMT3L68” has been revised to “…and maintain expression of the de novo methyltransferase–like protein DNMT3L68. Expression of DNMT3L appears to be a common feature in pluripotent cells including ES, EC and embryonic germ cells.” The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

J.J.C. would like to thank T. Dervieux for critical review and feedback on the manuscript. L.H.J.L. would like to thank J. Wolter Oosterhuis for the wonderful discussions of the last decades, significantly contributing to the work performed.

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Authors and Affiliations

  1. Department of Drug Safety Evaluation, Allergan Inc., Irvine, California, USA

    Justine J Cunningham

  2. Department of Pathology & Laboratory Medicine, Indiana University School of Medicine and Indiana University Health Partners, Indianapolis, Indiana, USA

    Thomas M Ulbright

  3. The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Florey Neurosciences Institutes, Melbourne, Victoria, Australia

    Martin F Pera

  4. Department of Pathology, Erasmus MC-University Medical Centre Rotterdam (Daniel den Hoed Cancer Centre), Josephine Nefkens Institute, Rotterdam, The Netherlands

    Leendert H J Looijenga

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Cunningham, J., Ulbright, T., Pera, M. et al. Lessons from human teratomas to guide development of safe stem cell therapies. Nat Biotechnol 30, 849–857 (2012). https://doi.org/10.1038/nbt.2329

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