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Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells
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- Shun Nakai
- School 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
- School 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
- School 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
- Isehara Research Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., 21 Suzukawa, Isehara, Kanagawa 259-1146, Japan
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- Nobuyuki Takagi
- Technology 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
- Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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- Toshito Nakagawa
- Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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- Jumpei Kiyokawa
- Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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- Satoshi Wakabayashi
- Pharmacokinetics 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
- Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc. 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan
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- Eriko Higashi
- Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc. 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan
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- Seiichi Ishida
- Division of Pharmacology, National Institute of Health Science, 3-25-26 Tonomati, Kawasaki 210-9501, Japan
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- Nobuaki Shiraki
- School 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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- Shoen Kume
- School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Description
<jats:p>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 iPS cell-derived endoderm cells on collagen vitrigel membrane and compared with our previous reported nanofiber matrix.</jats:p><jats:p>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, 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 that 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.</jats:p><jats:p>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.</jats:p>
Journal
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- Biology Open
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Biology Open 8 20-, 2019-01-01
The Company of Biologists
