1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

  1. Takeshi Katsuda
  2. Juntaro Matsuzaki
  3. Tomoko Yamaguchi
  4. Yasuhiro Yamada
  5. Marta Prieto-Vila
  6. Kazunori Hosaka
  7. Atsuko Takeuchi
  8. Yoshimasa Saito
  9. Takahiro Ochiya  Is a corresponding author
  1. National Cancer Center Research Institute, Japan
  2. Nihon Pharmaceutical University, Japan
  3. Kobe Pharmaceutical University, Japan
  4. Keio University, Japan
Research Article
  • Cited 13
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Cite this article as: eLife 2019;8:e47313 doi: 10.7554/eLife.47313

Abstract

Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

Data availability

Microarray transcriptome data are available with accession numbers GSE133776 (Reprogramming of primary human hepatocytes (PHHs) into hCLiPs); GSE133777 (Hepatic induction of hCLiPs); GSE133778(Characterization of long term-cultured of hCLiPs); GSE133779 (Transcriptomic analysis of PHHs isolated from hCLiP-transplanted mouse chimeric liver). GSE133776-GSE133779 are included in Superseries GSE133797. Comparative analysis of IPHH and APHH transcriptome is available with an accession number GSE134672.

The following data sets were generated

Article and author information

Author details

  1. Takeshi Katsuda

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    Competing interests
    No competing interests declared.

  2. Juntaro Matsuzaki

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3204-5049

  3. Tomoko Yamaguchi

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    Competing interests
    No competing interests declared.

  4. Yasuhiro Yamada

    Department of Clinical Pharmaceutics, Nihon Pharmaceutical University, Saitama, Japan
    Competing interests
    No competing interests declared.

  5. Marta Prieto-Vila

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    Competing interests
    No competing interests declared.

  6. Kazunori Hosaka

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    Competing interests
    No competing interests declared.

  7. Atsuko Takeuchi

    Division of Analytical Laboratory, Kobe Pharmaceutical University, Kobe, Japan
    Competing interests
    No competing interests declared.

  8. Yoshimasa Saito

    Division of Pharmacotherapeutics, Keio University, Tokyo, Japan
    Competing interests
    No competing interests declared.

  9. Takahiro Ochiya

    Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
    For correspondence
    tochiya@ncc.go.jp
    Competing interests
    Takahiro Ochiya, Received funding from Interstem Co. Ltd..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0776-9918

Funding

Japan Agency for Medical Research and Development (16fk0310512h0005)

  • Takahiro Ochiya

Japan Agency for Medical Research and Development (17fk0310101h0001)

  • Takahiro Ochiya

Japan Society for the Promotion of Science London (16K16643)

  • Takeshi Katsuda

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments in this study were performed in compliance with the guidelines of the Institute for Laboratory Animal Research, National Cancer Center Research Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments of National Cancer Center Research Institute (Permit Number: T14-015-E). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Hao Zhu, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: April 1, 2019
  2. Accepted: August 8, 2019
  3. Accepted Manuscript published: August 8, 2019 (version 1)
  4. Version of Record published: September 6, 2019 (version 2)

Copyright

© 2019, Katsuda et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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