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  • Review Article
  • Published:

Genetic and epigenetic stability of human pluripotent stem cells

Nature Reviews Genetics volume 13, pages 732–744 (2012)Cite this article

Subjects

Key Points

  • Recent studies that exploit novel high-resolution genome-wide approaches have reported frequent accumulation of genomic and epigenomic alterations in human pluripotent cells that can affect multiple properties and compromise their quality or use. Importantly, severe safety concerns arise when considering the use of these cells in regenerative therapies.

  • On the basis of recent large-scale meta-analysis, the most recurrent genomic change in both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) is amplification of chromosome 12. Other commonly detected changes are at chromosomes 8, 12p, i(20)q10 and X. The most recurrent copy number variant (CNV) is amplification of at 20q11.21.

  • Trisomy of chromosome 17, which is common in hESCs, has not been observed in hiPSCs. Instead, trisomy of chromosome 8 is detected more often in hiPSCs than in hESCs.

  • On the basis of current knowledge, genomic stability of hiPSCs is not dependent of the method used for reprogramming. However, the reprogramming process has been reported to induce genomic and epigenetic changes. Importantly, early passages of hiPSCs can consist of mosaic populations of cells.

  • The epigenome of hESCs is highly dynamic and sensitive to variation. Variation and instability in imprinting, X-chromosome inactivation and DNA methylation of developmental and cancer genes has been reported in different conditions.

  • hiPSCs have been reported to be highly similar to hESCs for their epigenomic profiles. However, often hiPSCs may also show remnants of the epigenomic memory from somatic parent cells and sometimes activate abnormal pattern of genes or show higher methylation levels compared to the hESCs.

  • Importantly, careful and frequent monitoring of the cells is required to ensure the genomic integrity of the cells, as unidentified aberrations may lead to distorted results and may raise safety issues for therapeutic use.

  • Future integrative approaches exploiting genome-wide sequencing techniques will supplement and provide valuable and comprehensive information on the genomic and epigenomic integrity of pluripotent cells and their derivates.

Abstract

Studies using high-resolution genome-wide approaches have recently reported that genomic and epigenomic alterations frequently accumulate in human pluripotent cells. Detailed characterization of these changes is crucial for understanding the impact of these alterations on self-renewal and proliferation, and particularly on the developmental and malignant potential of the cells. Such knowledge is required for the optimized and safe use of pluripotent cells for therapeutic purposes, such as regenerative cellular therapies using differentiated derivatives of pluripotent cells.In this Review, we summarize the current knowledge of the genomic and epigenomic stability of pluripotent human cells and the implications for stem cell research.

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Figure 1: The most frequent genomic changes in human pluripotent stem cells.
Figure 2: The incidence of genomic changes during passaging.
Figure 3: Genomic and epigenomic aberrations can occur at multiple steps of pluripotent cell maintenance.

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Acknowledgements

The work was supported by the Academy of Finland, Centre of Excellence in Molecular Systems Immunology and Physiology Research, 2012–2017, decision number 250114, and grant 116713, the Finnish Cancer Organizations, Turku University Hospital Grant, Turku University Foundation, Turku Doctoral Programme of Biomedical Sciences and Biocenter Finland.

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Author notes

  1. Riikka J. Lund and Elisa Närvä: These authors contributed equally to this work.

Authors and Affiliations

  1. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FIN-20520, Finland

    Riikka J. Lund, Elisa Närvä & Riitta Lahesmaa

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  1. Riikka J. Lund
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  2. Elisa Närvä
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  3. Riitta Lahesmaa
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Correspondence to Riitta Lahesmaa.

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Glossary

DNA methylation

DNA modification in which a methyl group is added to the 5 position of the cytosine base.

Karyotypes

The appearance of the chromosomes in a cell with reference to their number, size, shape, structure, length, the position of the centromeres, banding pattern, any differences between the sex chromosomes and any other physical characteristics.

Giemsa banding

(G-banding). One of several methods for staining chromosomes; it produces light and dark bands that are characteristic for each homologous chromosome pair, so that individual chromosomes can be distinguished and examined for abnormalities in structure and number.

Mosaic

An organism or cell population that consists of cells of more than one genotype.

Uniparental disomy

A cellular or organismal phenomenon in which both chromosome homologues are derived from one parent with none derived from the other parent. It can be the result of fertilization involving a disomic gamete and a gamete that is nullisomic for the homologue.

Passage numbers

The numbers of division rounds of subculturing of the cultured cells.

Bivalent chromatin

The co-occurrence of histone tail methylation marks that are associated with both transcriptional activation (such as histone H3 trimethylated on lysine 4 (H3K4me3)) and repression (such as H3K27me3). Bivalency is observed in mammalian embryonic stem cells at developmentally important genes.

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Lund, R., Närvä, E. & Lahesmaa, R. Genetic and epigenetic stability of human pluripotent stem cells. Nat Rev Genet 13, 732–744 (2012). https://doi.org/10.1038/nrg3271

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