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Transdifferentiation of human fibroblasts into hepatocyte-like cells by defined transcriptional factors

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Abstract

Purpose

Liver transplantation is currently the only curative therapeutic option for end-stage liver cirrhosis. However, due to the limitations of donor liver availability and occasional rejection, it cannot always be successfully applied. In this study, we determined whether fibroblasts can be transdifferentiated into hepatocyte-like cells by transcription factors that initiate and maintain hepatocyte differentiation.

Methods

Fibroblasts were transduced with retrovirus vectors carrying FOXA2, HNF4α, and C/EBPβ. To enhance the efficiency of transdifferentiation, cMyc was also expressed.

Results

Transdifferentiation was successful using both neonatal fibroblasts and human forehead fibroblasts. The transdifferentiated cells produced hepatocyte-specific proteins such as albumin and cytochrome, and had important hepatocyte-specific functions, such as glycogen storage and indocyanine green uptake, suggesting that the cells function at least as partial hepatocytes.

Conclusions

These results provide a novel method of generating differentiated hepatocyte-like cells, and may represent an alternative source of cells for future cell-based therapeutics for end-stage liver diseases.

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Acknowledgements

We would like to thank all the members of Dowdy lab for their helpful advice and support in carrying out these experiments. This work was supported by a Nakayama Cancer Research Institute Scholarship, an Itoe Okamoto Scholarship Grant, and the Hisako Yamakawa Award at Tokyo Women’s Medical University to T. K.

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Tomomi Kogiso & Keiko Shiratori

  2. Aoyama Hospital, Tokyo Women’s Medical University, 2-7-13 Kita-Aoyama, Minato-ku, Tokyo, 107-0061, Japan

    Hikaru Nagahara

  3. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Motoyuki Otsuka

  4. Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0686, USA

    Steven F. Dowdy

Authors
  1. Tomomi Kogiso
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  2. Hikaru Nagahara
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  3. Motoyuki Otsuka
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  4. Keiko Shiratori
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  5. Steven F. Dowdy
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Correspondence to Tomomi Kogiso.

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Kogiso, T., Nagahara, H., Otsuka, M. et al. Transdifferentiation of human fibroblasts into hepatocyte-like cells by defined transcriptional factors. Hepatol Int 7, 937–944 (2013). https://doi.org/10.1007/s12072-013-9432-5

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  • DOI: https://doi.org/10.1007/s12072-013-9432-5

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