Original Article | Published:

Defining the nature of human pluripotent stem cell progeny

Cell Research volume 22, pages 178193 (2012) | Download Citation

Abstract

While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissue-derived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

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Acknowledgements

We are grateful to Eric Wexler and Heather Martin for assistance in the acquisition of fetal tissues; to Margaret Baron for sharing the AFP-GFP reporter; to Soheila Azghadi, Hung Trinh, Otaren Aimiuwu, Kimberly Loo and Adelaja Akinlolou for technical support; and to Mark Chin and Raj Sasidharan for assistance with bioinformatic analyses. We would like to acknowledge the core facilities at the UCLA including: FACS (Felicia Cordea and Jessica Scholes); the Clinical Microarray Core (Xinmin Li and Jian Zhou); and the hiPSC and hESC Cores. MP was supported by the Training Program in Genetic Mechanisms (GM007104-33). MP and DC were supported by Predoctoral Training Grants from CIRM at EEBSCRC (TG2-01169). This work was supported by a seed grant from CIRM (RS1-00259-1), a Basil O'Connor Starter Scholar Award (5-FY09-61), and the Fuller Foundation at EEBSCRC (WEL). WEL holds the Maria Rowena Ross Chair in Cell Biology and Biochemistry.

Author information

Author notes

    • Michaela Patterson
    •  & David N. Chan

    These two authors contributed equally to this work.

Affiliations

  1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA

    • Michaela Patterson
    • , David N. Chan
    • , Iris Ha
    • , Yongyan Cui
    • , Ben Van Handel
    • , Hanna KA Mikkola
    •  & William E Lowry
  2. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA

    • Hanna KA Mikkola
    •  & William E Lowry
  3. Eli and Edythe Broad Center for Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA

    • Michaela Patterson
    • , David N. Chan
    • , Ben Van Handel
    • , Hanna KA Mikkola
    •  & William E Lowry
  4. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA

    • Dana Case
    • , Hanna KA Mikkola
    •  & William E Lowry

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Corresponding author

Correspondence to William E Lowry.

Supplementary information

PDF files

  1. 1.

    Supplementary information, Figure S1

    hESC and hiPSC lines make cell types representing all three germ layers.

  2. 2.

    Supplementary information, Figure S2

    Gene expression differences between PSC and tissue derivatives are conserved regardless of statistical analyses employed or lab.

  3. 3.

    Supplementary information, Table 1

    Expression of pluripotency genes across samples.

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DOI

https://doi.org/10.1038/cr.2011.133

(Supplementary information is linked to the online version of the paper on the Cell Research website.)

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