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Research Article
Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells
Shun Nakai, Ima Shibata, Takahiro Shitamichi, Hiroyuki Yamaguchi, Nobuyuki Takagi, Tomoaki Inoue, Toshito Nakagawa, Jumpei Kiyokawa, Satoshi Wakabayashi, Tomoya Miyoshi, Eriko Higashi, Seiichi Ishida, Nobuaki Shiraki, Shoen Kume
Biology Open 2019 8: bio042192 doi: 10.1242/bio.042192 Published 2 July 2019
Shun Nakai
1School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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Ima Shibata
1School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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Takahiro Shitamichi
1School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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Hiroyuki Yamaguchi
2Isehara Research Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., 21 Suzukawa, Isehara, Kanagawa 259-1146, Japan
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Nobuyuki Takagi
3Technology and Development Division, Kanto Chemical Co., Inc., 2-1, Nihonbashi Muromachi 2-chome, Chuo-ku, Tokyo 103-0022, Japan
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Tomoaki Inoue
4Research Division, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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Toshito Nakagawa
4Research Division, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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Jumpei Kiyokawa
4Research Division, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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Satoshi Wakabayashi
5Pharmacokinetics and Metabolism, Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Saitama-shi, Saitama 330-8530, Japan
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Tomoya Miyoshi
6Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan
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Eriko Higashi
6Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan
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Seiichi Ishida
7Division of Pharmacology, National Institute of Health Science, 3-25-26 Tonomati, Kawasaki 210-9501, Japan
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Nobuaki Shiraki
1School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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  • ORCID record for Nobuaki Shiraki
  • For correspondence: skume@bio.titech.ac.jp shiraki@bio.titech.ac.jp
Shoen Kume
1School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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  • For correspondence: skume@bio.titech.ac.jp shiraki@bio.titech.ac.jp
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ABSTRACT

Differentiation of stem cells to hepatocytes provides an unlimited supply of human hepatocytes and therefore has been vigorously studied. However, to date, the stem cell-derived hepatocytes were suggested to be of immature features. To obtain matured hepatocytes from stem cells, we tested the effect of culturing human-induced pluripotent stem (hiPS) cell-derived endoderm cells on collagen vitrigel membrane and compared with our previous reported nanofiber matrix. We cultured hiPS cell-derived endoderm cells on a collagen vitrigel membrane and examined the expression profiles, and tested the activity of metabolic enzymes. Gene expression profile analysis of hepatocytic differentiation markers revealed that upon culture on collagen vitrigel membrane, immature markers of AFP decreased, with a concomitant increase in the expression of mature hepatocyte transcription factors and mature hepatocyte markers such as ALB, ASGR1. Mature markers involved in liver functions, such as transporters, cytochrome P450 enzymes and phase II metabolic enzymes were also upregulated. We observed the upregulation of the liver markers for at least 2 weeks. Gene array profiling analysis revealed that hiPS cell-derived hepatocyte-like cells (hiPS-hep) resemble those of the primary hepatocytes. Functions of the CYP enzyme activities were tested in multi-institution and all revealed high CYP1A, CYP2C19, CYP2D6, CYP3A activity, which could be maintained for at least 2 weeks in culture. Taken together, the present approach identified that collagen vitrigel membrane provides a suitable environment for the generation of hepatocytes from hiPS cells that resemble many characteristics of primary human hepatocytes.

Footnotes

  • Competing interests

    H.Y. and N.T. are employees in Kanto Chemical Co. Inc., which supplies collagen vitrigel membrane products.

  • Author contributions

    Conceptualization: S.N., N.S., S.K.; Methodology: S.N., H.Y., N.S., S.K.; Validation: S.N., I.S., T.S., H.Y., N.T., T.I., T.N., J.K., S.W., T.M., E.H., S.I., N.S., S.K.; Formal analysis: S.N., H.Y., T.I., T.N., J.K., S.W., T.M., E.H., N.S., S.K.; Investigation: S.N., I.S., T.S., H.Y., N.T., T.I., T.N., J.K., S.W., T.M., E.H., N.S., S.K.; Resources: N.T., N.S., S.K.; Data curation: H.Y., T.I., T.N., J.K., S.W., T.M., E.H., S.I., N.S., S.K.; Writing - original draft: S.K.; Writing - review & editing: I.S., T.S., H.Y., N.T., T.I., T.N., J.K., S.W., T.M., E.H., S.I., N.S., S.K.; Visualization: S.K.; Supervision: N.S., S.K.; Project administration: N.S., S.K.; Funding acquisition: S.K.

  • Funding

    This work was supported by a grant from Japan Agency for Medical Research and Development (AMED) (to S.K., Grant no. 18bk0104075h0102).

  • Data availability

    Data can be found at the Dryad Digital Repository: https://datadryad.org/resource/doi:10.5061/dryad.5f3s52r/1.

  • Supplementary information

    Supplementary information available online at http://bio.biologists.org/lookup/doi/10.1242/bio.042192.supplemental

  • Received February 1, 2019.
  • Accepted May 19, 2019.
  • © 2019. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Hepatocytic differentiation
  • In vitro differentiation
  • Induced pluripotent stem cells

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Research Article
Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells
Shun Nakai, Ima Shibata, Takahiro Shitamichi, Hiroyuki Yamaguchi, Nobuyuki Takagi, Tomoaki Inoue, Toshito Nakagawa, Jumpei Kiyokawa, Satoshi Wakabayashi, Tomoya Miyoshi, Eriko Higashi, Seiichi Ishida, Nobuaki Shiraki, Shoen Kume
Biology Open 2019 8: bio042192 doi: 10.1242/bio.042192 Published 2 July 2019
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Research Article
Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells
Shun Nakai, Ima Shibata, Takahiro Shitamichi, Hiroyuki Yamaguchi, Nobuyuki Takagi, Tomoaki Inoue, Toshito Nakagawa, Jumpei Kiyokawa, Satoshi Wakabayashi, Tomoya Miyoshi, Eriko Higashi, Seiichi Ishida, Nobuaki Shiraki, Shoen Kume
Biology Open 2019 8: bio042192 doi: 10.1242/bio.042192 Published 2 July 2019

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