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Differentiation of human iPS cells into hepatocytes and enterocytes: Development of first pass effect assessment model

Research Project

Project/Area Number 26293036
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionNagoya City University

Principal Investigator

Matsunaga Tamihide  名古屋市立大学, 薬学研究科(研究院), 教授 (40209581)

Co-Investigator(Kenkyū-buntansha) 大森 栄  信州大学, 医学部附属病院, 教授 (70169069)
永田 清  東北医科薬科大学, 薬学部, 教授 (80189133)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2014: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
KeywordsヒトiPS細胞 / 分化誘導 / 肝細胞 / 腸管上皮細胞 / 初回通過効果 / 薬物代謝酵素 / 薬物トランスポーター / 薬物動態 / 経口バイオアベイラビリティ / デバイス / 薬学 / iPS細胞 / 分化 / 薬物動態学 / 人工多能性幹細胞 / 薬物代謝 / トランスポーター / 低分子化合物 / スクラーゼ・イソマルターゼ
Outline of Final Research Achievements

Human induced pluripotent stem (iPS) cells are expected to be applicable not only in regenerative medicine but also in drug development such as pharmacokinetic and toxicokinetic studies. In this study, the differentiation in 3D sphere culture was increased the gene expressions or the activity of drug metabolizing enzymes and improved the function of human iPS cell-derived hepatocytes. The small-molecule compounds, PD98059, 5-aza-2-deoxycytidine and A-83-01, were effective in generating pharmacokinetically functional enterocytes from human iPS cells. MEK, DNMT, and TGF-β inhibitors can be used to promote the differentiation of human iPS cells into pharmacokinetically functional enterocytes.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (46 results)

All 2017 2016 2015 2014

All Journal Article (12 results) (of which Peer Reviewed: 10 results,  Open Access: 8 results,  Acknowledgement Compliant: 3 results) Presentation (30 results) (of which Int'l Joint Research: 2 results,  Invited: 6 results) Book (1 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Functional Analysis of Carboxylesterase in Human Induced Pluripotent Stem Cell-derived Enterocytes.2017

    • Author(s)
      Kabeya T, Matsumura W, Iwao T, Hosokawa M, Matsunaga T
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 486 Issue: 1 Pages: 143-148

    • DOI

      10.1016/j.bbrc.2017.03.014

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Application of a human intestinal epithelial cell monolayer to the prediction of oral drug absorption in humans as a superior alternative to the Caco-2 cell monolayer.2016

    • Author(s)
      Takenaka T, Harada N, Kuze J, Chiba M, Iwao T, Matsunaga T
    • Journal Title

      J Pharm Sci

      Volume: 105 Issue: 1 Pages: 915-924

    • DOI

      10.1016/j.dmpk.2016.08.004

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of mitogen-activated protein kinase kinase, DNA methyltransferase, and transforming growth factor-β promotes differentiation of human induced pluripotent stem cells into enterocytes2016

    • Author(s)
      Kodama N, Iwao T, Kabeya T, Horikawa T, Niwa T, Kondo Y, Nakamura K, Matsunaga T
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: in press Issue: 3 Pages: 193-200

    • DOI

      10.1016/j.dmpk.2016.02.002

    • NAID

      50014431261

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characteristic analysis of intestinal absorption in enterocyte-like cells differentiated from human induced pluripotent stem cells.2016

    • Author(s)
      Kodama N, Iwao T, Ohta K, Yuasa H, Matsunaga T
    • Journal Title

      Drug Metab. Dispos.

      Volume: 44 Issue: 10 Pages: 1662-1667

    • DOI

      10.1124/dmd.116.069336

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ヒトiPS細胞の分化誘導の現状と創薬研究への応用2016

    • Author(s)
      岩尾岳洋,松永民秀
    • Journal Title

      HAB Newsletter

      Volume: 22 Pages: 6-7

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Application of a human intestinal epithelial cell monolayer to the prediction of oral drug absorption in humans as a superior alternative to the Caco-2 cell monolayer2016

    • Author(s)
      Takenaka T, Harada N, Kuze J, Chiba M, Iwao T, Matsunaga T
    • Journal Title

      J Pharm Sci

      Volume: 105 Issue: 2 Pages: 915-924

    • DOI

      10.1016/j.xphs.2015.11.035

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation of enterocyte-like cells with pharmacokinetic functions from human induced pluripotent stem cells using small-molecule compounds2015

    • Author(s)
      Iwao T, Kodama N, Kondo Y, Kabeya T, Nakamura K, Horikawa T, Niwa T, Kurose K, Matsunaga T
    • Journal Title

      Drug Metab Dispos

      Volume: 43 Issue: 4 Pages: 603-610

    • DOI

      10.1124/dmd.114.062604

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 個別化(オーダーメイド)医療を志向した薬物動態研究及び毒性試験へのヒトiPS細胞の利用2015

    • Author(s)
      岩尾岳洋、松永民秀
    • Journal Title

      Organ Biology

      Volume: 22 Pages: 39-48

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Histone deacetylase inhibitor valproic acid promotes the differentiation of human induced pluripotent stem cells into hepatocyte-like cells.2014

    • Author(s)
      Kondo Y, Iwao T, Yoshihashi S, Mimori K, Ogihara R, Nagata K, Kurose K, Saito M, Niwa T, Suzuki T, Miyata N, Ohmori S, Nakamura K, Matsunaga T.
    • Journal Title

      PLoS One.

      Volume: 9 Issue: 8 Pages: 1-11

    • DOI

      10.1371/journal.pone.0104010

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Selective culture method for hepatocyte-like cells differentiated from human induced pluripotent stem cells.2014

    • Author(s)
      Kondo Y, Yoshihashi S, Mimori K, Ogihara R, Kanehama Y, Maki Y, Enosawa S, Kurose K, Iwao T, Nakamura K, Matsunaga T
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 29 Pages: 407-413

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity.2014

    • Author(s)
      Kondo Y, Iwao T, Nakamura K, Sasaki T, Takahashi S, Kamada N, Matsubara T, Gonzalez FJ, Akutsu H, Miyagawa Y, Okita H, Kiyokawa N, Toyoda M, Umezawa A, Nagata K, Matsunaga T, Ohmori S
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 29 Pages: 237-243

    • NAID

      130004463382

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differentiation of human induced pluripotent stem cells into functional enterocyte-like cells using a simple method.2014

    • Author(s)
      Iwao T, Toyota M, Miyagawa Y, Okita H, Kiyokawa N, Akutsu H, Umezawa A, Nagata K, Matsunaga T
    • Journal Title

      Drug Metab Pharmacokinet

      Volume: 29 Pages: 44-51

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 消化管の薬物動態及び毒性試験における新規創薬研究支援材料.2017

    • Author(s)
      松永民秀
    • Organizer
      第31回日本薬物動態学会年会 ランチョンセミナー講演
    • Place of Presentation
      松本
    • Year and Date
      2017-10-13
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS細胞由来腸管上皮細胞におけるカルボキシエステラーゼの機能解析.2017

    • Author(s)
      壁谷知樹,松村若菜,岩尾岳洋,細川正清,松永民秀
    • Organizer
      第137年会日本薬学会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] 異種間キメラマウス作出方法がラットES細胞のマウス肝臓への寄与に与える影響.2017

    • Author(s)
      中西杏菜,奥村啓樹,山野上 舞,山田果奈,宮本智美,平林真澄,田川陽一,坡下真大,岩尾岳洋,松永民秀
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] 基底膜成分を用いたヒトiPS細胞由来小腸幹細胞の単離.2017

    • Author(s)
      邱 施萌,長崎瑞佳,壁谷知樹,岩尾岳洋,松永民秀
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] カニクイザルiPS細胞由来腸管オルガノイドの長期培養.2017

    • Author(s)
      木田有里子,小野里太智,赤川 巧,小枝暁子,岩尾岳洋,松永民秀
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] カニクイザルiPS細胞由来腸管オルガノイドを用いた薬物動態学的機能解析.2017

    • Author(s)
      小野里太智,山下美紗季,木田有里子,小枝暁子,岩尾岳洋,松永民秀
    • Organizer
      シンポジウム:細胞アッセイ技術の現状と将来
    • Place of Presentation
      東京
    • Related Report
      2016 Annual Research Report
  • [Presentation] マイクロカプセル内でのヒトiPS細胞由来肝細胞の作製.2017

    • Author(s)
      大西 琢,小野里太智,岩尾岳洋,境 慎司,田谷正仁,松永民秀
    • Organizer
      シンポジウム:細胞アッセイ技術の現状と将来
    • Place of Presentation
      東京
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトiPS細胞由来腸管オルガノイドの機能評価.2017

    • Author(s)
      山下美紗季,小野里太智,赤川 巧,岩尾岳洋,松永民秀
    • Organizer
      シンポジウム:細胞アッセイ技術の現状と将来
    • Place of Presentation
      東京
    • Related Report
      2016 Annual Research Report
  • [Presentation] 創薬研究支援材料として期待されるヒトiPS細胞の利用法.2017

    • Author(s)
      松永民秀
    • Organizer
      医薬品等規制調和・評価研究事業 合同公開シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 量子ドットを用いた移植肝細胞の蛍光イメージング.2016

    • Author(s)
      奥村啓樹,名仁澤英里,中西杏菜,湯川 博,石川哲也,坡下真大,岩尾岳洋,松永民秀
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトiPS細胞の肝細胞への分化誘導における浮遊培養培地の比較.2016

    • Author(s)
      阿武志保,奥村啓樹,坡下真大,林 寿人,岩尾岳洋,金木達朗,松永民秀
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] 胚盤胞注入法と8細胞期胚注入法が異種動物間キメラ率に与える影響.2016

    • Author(s)
      山野上舞,山田果奈,中西杏菜,奥村啓樹,宮本智美,平林真澄,坡下真大,岩尾岳洋,松永民秀
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Generation of functional cynomolgus monkey iPS cell-derived intestinal organoids.2016

    • Author(s)
      Onozato D, Akagawa T, Yamashita M, Kida Y, Koeda A, Iwao T, Matunaga T
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] Microencapsulation of human induced pluripotent stem cell-derived hepatocytes.2016

    • Author(s)
      Onish T, Onozato D, Iwao T, Sakai S, Taya M, Matsunaga T
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトiPS細胞からの腸管オルガノイドの作製.2016

    • Author(s)
      山下美紗季,小野里太智,赤川 巧,岩尾岳洋,松永民秀
    • Organizer
      日本薬物動態学会 第31回年会
    • Place of Presentation
      松本
    • Year and Date
      2016-10-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] Small molecule compounds enhance the differentiation of human induced pluripotent stem cells to enterocytes with pharmacokinetic functions.2016

    • Author(s)
      Kabeya T, Iwao T, Kodama N, Matsunaga T
    • Organizer
      11th International ISSX Meeting
    • Place of Presentation
      釜山、韓国
    • Year and Date
      2016-06-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒトiPS細胞由来腸管上皮細胞モデルにおける小腸特異的葉酸トランスポーター機能の検証.2016

    • Author(s)
      鈴木香帆, 片野貴大, 太田欣哉, 保嶋智也, 壁谷知樹, 小玉菜央, 岩尾岳洋, 松永民秀, 湯浅博昭
    • Organizer
      日本薬剤学会第31年会
    • Place of Presentation
      岐阜
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] 消化管毒性評価系の構築を目指したヒトiPS細胞/カニクイザルES細胞由来腸管上皮様細胞及びオルガノイドの作製2016

    • Author(s)
      小野里太智,福山了介,赤川 巧,小枝暁子,岩尾岳洋,松永民秀
    • Organizer
      細胞アッセイ研究会シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2016-01-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトiPS細胞から肝細胞への低分子化合物を用いた分化誘導.シンポジウム2016

    • Author(s)
      松永民秀,栗木駿輔,坂本 栄,岩尾岳洋
    • Organizer
      細胞アッセイ研究会シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2016-01-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] 新規三次元培養培地を用いた浮遊培養法でのヒトiPS細胞から肝細胞への分化誘導2015

    • Author(s)
      阿武志保,岩尾岳洋,金木達朗,松永民秀
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] カニクイザル胚性幹細胞から腸管上皮細胞様細胞の作製2015

    • Author(s)
      福山了介,小野里太智,小枝暁子,岩尾岳洋,松永民秀
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト人工多能性幹細胞から分化誘導した腸管上皮様細胞の薬物動態学的特性解析2015

    • Author(s)
      小玉菜央,岩尾岳洋,壁谷知樹,中村克徳,松永民秀
    • Organizer
      日本薬物動態学会第30回年会
    • Place of Presentation
      東京
    • Year and Date
      2015-11-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト人工多能性幹細胞の腸管への分化に対する低分子化合物の有用性2015

    • Author(s)
      壁谷知樹,岩尾岳洋,小玉菜央,中村克徳,松永民秀
    • Organizer
      日本薬物動態学会第30回年会
    • Place of Presentation
      東京
    • Year and Date
      2015-11-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト人工多能性幹細胞由来腸管上皮細胞の薬物動態学的機能評価2015

    • Author(s)
      岩尾岳洋,小玉菜央,壁谷知樹,松永民秀
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部 合同学術大会2015
    • Place of Presentation
      名古屋
    • Year and Date
      2015-11-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトiPS細胞の創薬研究への応用:肝細胞及び腸管上皮細胞への誘導と機能2015

    • Author(s)
      松永民秀
    • Organizer
      医療薬学フォーラム2015/第23回クリニカルファーマシーシンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2015-07-04
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 低分子化合物によるヒトiPS細胞から機能的な腸管上皮細胞への分化促進2015

    • Author(s)
      小玉菜央,岩尾岳洋,壁谷知樹,中村克徳,松永民秀
    • Organizer
      第22回HAB研究機構学術年会シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2015-06-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] Utility of iPS cells for study of drug metabolism and pharmacokinetics: Differentiation of human iPS cells into hepatocytes and enterocytes.2015

    • Author(s)
      Matsunaga T
    • Organizer
      The 19th International Conference on Cytochrome P450
    • Place of Presentation
      東京
    • Year and Date
      2015-06-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Utility of iPS cells for drug metabolizing enzyme expression.2014

    • Author(s)
      Matsunaga T
    • Organizer
      19th North American ISSX joint meeting
    • Place of Presentation
      San Francisco, CA, USA
    • Year and Date
      2014-10-19 – 2014-10-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS細胞の創薬研究への応用2014

    • Author(s)
      松永民秀
    • Organizer
      製剤機械技術学会第24回大会一般講演
    • Place of Presentation
      名古屋
    • Year and Date
      2014-10-08 – 2014-10-09
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS細胞由来小腸幹細胞の至適培養法の開発.2014

    • Author(s)
      壁谷知樹,岩尾岳洋,小玉菜央,中村克徳,松永民秀
    • Organizer
      第66回日本生物工学会大会
    • Place of Presentation
      札幌
    • Year and Date
      2014-09-09 – 2014-09-11
    • Related Report
      2014 Annual Research Report
  • [Book] 薬剤学実験法 必携マニュアル―Pharmaceutical Scientistのために― II 生物薬剤学2014

    • Author(s)
      松永民秀,岩尾岳洋
    • Total Pages
      12
    • Publisher
      南江堂
    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] 化学物質評価用のデバイス、および、化学物質評価方法2017

    • Inventor(s)
      松永民秀、岩尾岳洋、近藤聡志、土井淳史
    • Industrial Property Rights Holder
      松永民秀、岩尾岳洋、近藤聡志、土井淳史
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-006873
    • Filing Date
      2017-01-18
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 人工多能性幹細胞由来腸管幹細胞の維持培養2017

    • Inventor(s)
      松永民秀、岩尾岳洋、近藤聡志
    • Industrial Property Rights Holder
      松永民秀、岩尾岳洋、近藤聡志
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-029448
    • Filing Date
      2017-02-20
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 人工多能性幹細胞の腸管上皮細胞への分化誘導2017

    • Inventor(s)
      松永民秀、岩尾岳洋、壁谷知樹
    • Industrial Property Rights Holder
      松永民秀、岩尾岳洋、壁谷知樹
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017-03-03
    • Related Report
      2016 Annual Research Report
    • Overseas

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Published: 2014-04-04   Modified: 2018-03-22  

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