A Call to Standardize Teratoma Assays Used to Define Human Pluripotent Cell Lines

Müller, Franz‐Josef; Goldmann, Johanna; Löser, Peter; Loring, Jeanne F.

doi:10.1016/j.stem.2010.04.009

Cited by 127 publications

(119 citation statements)

References 9 publications

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“…Teratoma formation assay has been used as a routine test of pluripotency of ESCs/iPSCs, and is regarded as a gold standard for evaluation of human ESC/iPSC pluripotency [31][32][33][34][35], because chimera and germline transmission tests are not ethically feasible. We show that telomerase-deficient mouse ESCs with short telomeres form teratomas as efficiently as WT ESCs with long telomeres, but exhibit decreased pluripotency by the stringent tests, i.e.…”

Section: Discussionmentioning

confidence: 99%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells (iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells (ESCs) or iPSCs, however, has not been directly addressed. We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated (r > 0.8) with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics, down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible.

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Section: Discussionmentioning

confidence: 99%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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“…3) In general, to demonstrate the pluripotency of established cells, they are injected into immunodeficient mice, e.g., nude mice, to form spontaneous teratomas. Teratomas are defined as tumors of multiple lineages containing tissue derived from the three germ layers (i.e., endoderm, mesoderm, and ectoderm).…”

Section: The Tumorigenicity Of Human Pluripo-tent Stem Cellsmentioning

confidence: 99%

Tumorigenicity Studies for Human Pluripotent Stem Cell-Derived Products

Kuroda

Yasuda

Sato

2013

Biological & Pharmaceutical Bulletin

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Human pluripotent stem cells (hPSCs), i.e. human embryonic stem cells and human induced pluripotent stem cells, are able to self-renew and differentiate into multiple cell types. Because of these abilities, numerous attempts have been made to utilize hPSCs in regenerative medicine/cell therapy. hPSCs are, however, also tumorigenic, that is, they can give rise to the progressive growth of tumor nodules in immunologically unresponsive animals. Therefore, assessing and managing the tumorigenicity of all final products is essential in order to prevent ectopic tissue formation, tumor development, and/or malignant transformation elicited by residual pluripotent stem cells after implantation. No detailed guideline for the tumorigenicity testing of hPSC-derived products has yet been issued for regenerative medicine/cell therapy, despite the urgent necessity. Here, we describe the current situations and issues related to the tumorigenicity testing of hPSC-derived products and we review the advantages and disadvantages of several types of tumorigenicity-associated tests. We also refer to important considerations in the execution and design of specific studies to monitor the tumorigenicity of hPSC-derived products.

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“…An example is the highly topical field of stem cell and pluripotency research. Even in this highly dynamic field, the old method of measuring teratoma formation in animals to ascertain pluripotency is hardly ever given up, even though modern (genetically-based) alternatives are available that work better than this animal experiment, in the sense that they povide richer and more quantitative data (Buta et al, 2013;Muller et al, 2010Muller et al, , 2008. For cases that require in vivo data in this area, a pluripotency test method is available that does not require growth of teratomas in mice.…”

Section: The Status Of Animal Experimentation In Europementioning

confidence: 99%