Letter | Published:

Influence of donor age on induced pluripotent stem cells

Nature Biotechnology volume 35, pages 6974 (2017) | Download Citation

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Abstract

Induced pluripotent stem cells (iPSCs) are being pursued as a source of cells for autologous therapies, many of which will be aimed at aged patients. To explore the impact of age on iPSC quality, we produced iPSCs from blood cells of 16 donors aged 21–100. We find that iPSCs from older donors retain an epigenetic signature of age, which can be reduced through passaging. Clonal expansion via reprogramming also enables the discovery of somatic mutations present in individual donor cells, which are missed by bulk sequencing methods. We show that exomic mutations in iPSCs increase linearly with age, and all iPSC lines analyzed carry at least one gene-disrupting mutation, several of which have been associated with cancer or dysfunction. Unexpectedly, elderly donors (>90 yrs) harbor fewer mutations than predicted, likely due to a contracted blood progenitor pool. These studies establish that donor age is associated with an increased risk of abnormalities in iPSCs and will inform clinical development of reprogramming technology.

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Acknowledgements

This work is supported by a Scripps Translational Science Institute pilot award (5 UL1 TR001114) from Scripps Genomic Medicine, a NIH-NCATS Clinical and Translational Science Award (CTSA; 5 UL1 RR025774) to STSI. Further support is provided by the NextGen Consortium NHLBI 5 U01 HL107436 to STSI and TSRI (E.J.T. and K.K.B.), and U54GM114833 to STSI (A.T.).

Author information

Author notes

    • Kristin K Baldwin
    •  & Ali Torkamani

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.

    • Valentina Lo Sardo
    • , William Ferguson
    •  & Kristin K Baldwin
  2. The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, California, USA.

    • Galina A Erikson
    • , Eric J Topol
    •  & Ali Torkamani

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Contributions

Conceptualization, K.K.B., A.T., E.J.T.; methodology, K.K.B., V.L.S., A.T.; formal analysis, A.T., G.A.E.; investigation, V.L.S., W.F., A.T.; resources, A.T., K.K.B., E.J.T.; writing—original draft, A.T., K.K.B.; writing—review and editing, K.K.B., V.L.S., W.F., A.T., E.J.T.; visualization, V.L.S., K.K.B., A.T.; supervision, A.T., K.K.B., E.J.T.; project administration, A.T., K.K.B., E.J.T.; funding acquisition, A.T., K.K.B., E.J.T.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kristin K Baldwin or Ali Torkamani.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4

Excel files

  1. 1.

    Supplementary Dataset 1

    CpG probes predictive of biological age.

  2. 2.

    Supplementary Dataset 2

    CpG probes associated with age of the donor.

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    Supplementary Dataset 3

    Somatic Mutation Coverage and Molecular Impact.

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    Supplementary Dataset 4

    Coverage and Somatic Mutation Counts.

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    Supplementary Dataset 5

    Somatic Mosaicism.

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DOI

https://doi.org/10.1038/nbt.3749

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