Establishment of hepatocyte model from induced pluripotent stem (iPS) cells for exploring uremic toxin production inhibitors

• Project/Area Number: 25670080
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: Saito Hideyuki 熊本大学, 医学部附属病院, 教授 (40225727)
• Co-Investigator(Kenkyū-buntansha): JONO Hirofumi 熊本大学, 医学部附属病院, 准教授 (40515483) ; SHIRAKI Nobuaki 東京工業大学, 生命理工学研究科, 准教授 (70448520)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 尿毒症物質 / 肝細胞 / iPS細胞 / 硫酸転移酵素 / 腎障害 / iPS / ヒト肝細胞 / 人工多能性幹細胞 / インドキシル硫酸 / 代謝スクリーニング

Outline of Final Research Achievements

This study aimed to establish a screening system for exploring inhibitors of uremic toxin production using human hepatocyte model cells derived from induced pluripotent stem (iPS) cells, as a hepatic production system for sulfate-conjugated uremic toxins. By using four different culture medium for differentiation induction, AFP-positive cells, a marker cell of prodromal hepatocyte, were detected 11 days after the culture initiation, thereby indicating that it was possible to induce the differentiation of endodermal frozen stock cells into genealogical hepatocytes. Newly established human hepatocytes from iPS cells could be a useful tool for screening inhibitors for indoxyl sulfate production in the human liver.

Research Products

• [Journal Article] Phase I and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated, advanced non-small cell lung cancer. (2015)
  • Author(s): Otani S, Hamada A, Sasaki J, Wada M, Yamamoto M, Ryuge S, Takakura A, Fukui T, Yokoba M, Mitsufuji H, Toyooka I, Maki S, Kimura M, Hayashi N, Ishihara M, Kasajima M, Hiyoshi Y, Katono K, Asakuma M, Igawa S, Kubota M, Katagiri M, Saito H, Masuda N.
  • Journal Title: Am J Clin Oncol. Volume: 38 Issue: 4 Pages: 405-410
  • DOI: 10.1097/coc.0b013e3182a2d98d
  • Peer Reviewed / Open Access
• [Journal Article] Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters. (2014)
  • Author(s): Saigo C, Nomura Y, Yamamoto Y, Sagata M, Matsunaga R, Jono H, Nishi K, Saito H.
  • Journal Title: Drug Des. Devel. Ther. Volume: 8 Pages: 1073-1082
  • DOI: 10.2147/dddt.s67456
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury. (2014)
  • Author(s): Saito H, Yoshimura M, Saigo C, Komori M, Nomura Y, Yamamoto Y, Sagata M, Wakida A, Chuman E, Nishi K, Jono H.
  • Journal Title: Toxicol. Sci. Volume: 141 Issue: 1 Pages: 206-217
  • DOI: 10.1093/toxsci/kfu119
  • NAID: 120005663611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Carbamazepine-imatinib interaction in a child with chronic myeloid leukemia. (2014)
  • Author(s): Taguchi K, Kouroki M, Ohmura T, Jono H, Endo F, Saito H.
  • Journal Title: Pediatr Int. Volume: 56
  • Peer Reviewed
• [Journal Article] Distinct interaction of nilotinib and imatinib with P-Glycoprotein in intracellular accumulation and cytotoxicity in CML Cell Line K562 cells. (2014)
  • Author(s): Yamakawa Y, Hamada A, Uchida T, Sato D, Yuki M, Hayashi M, Kawaguchi T, Saito H.
  • Journal Title: Biol Pharm Bull. Volume: 37 Pages: 1330-1335
  • NAID: 130004677542
  • Peer Reviewed
• [Journal Article] Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. (2014)
  • Author(s): Shiraki, N., Shiraki, Y., Tsuyama, T., Obata, F., Miura, M., Nagae, G., Aburatani, H., Kume, K., Endo, F., and Kume, S.
  • Journal Title: Cell Metab. Volume: 19 Issue: 5 Pages: 780-794
  • DOI: 10.1016/j.cmet.2014.03.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A synthetic nanofibrillar matrix promotes in vitro hepatic differentiation of embryonic stem cells and induced pluripotent stem cells. (2013)
  • Author(s): Yamazoe T, Shiraki N, Toyoda M, Kiyokawa N, Okita H, Miyagawa Y, Akutsu H, Umezawa A, Sasaki Y, Kume K, Kume S.
  • Journal Title: J Cell Sci. Volume: 126 Pages: 5391-5399
  • DOI: 10.1242/jcs.129767
  • Peer Reviewed
• [Presentation] Involvement of indoxyl sulfate in exacerbated susceptibility of streptozotocin (STZ)-induced (2015)
  • Author(s): Shimokawa Y, Oyama N, Kuwabara T, Mukoyama M, Jono H, Saito H
  • Organizer: 2015 American Society of Nephrology Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] Involvement of CYLD as a regulatory factor in fibrotic response of ischemic AKI kidney and hypoxic HK-2 cells (2015)
  • Author(s): Yoneda G, Suenaga N, Yabuuchi N, Nishi K, Jono H, Saito H
  • Organizer: 2015 American Society of Nephrology Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] 硫酸転移酵素（SULT）を標的とした従来にない腎保護・治療薬の開発 (2015)
  • Author(s): 山下真実、西郷智香、野村結衣、佐潟雅隆、米田剛、西一彦、城野博史、齋藤秀之
  • Organizer: 第55回日本臨床化学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-30
• [Presentation] 急性腎障害に伴う急性肺障害発症メカニズムにおけるインドキシル硫酸の関与 (2015)
  • Author(s): 米田剛、薮内希実、佐潟雅隆、西郷智香、西一彦、城野博史、齋藤秀之
  • Organizer: 第55回日本臨床化学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-30
• [Presentation] 硫酸転移酵素（SULT）を標的とした新規腎保護・治療薬の開発 (2015)
  • Author(s): 西郷智香、野村祐衣、米田剛、山本悠子、城野博史、齋藤秀之
  • 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
  • Invited
• [Presentation] CKD 病態進展における慢性炎症制御因子CYLD の病態生理学的意義 (2015)
  • Author(s): 米田剛、末永尚輝、薮内希実、西一彦、城野博史、齋藤秀之
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-06-05
• [Presentation] 腎疾患・尿毒症における薬剤適正使用と治療薬探索の動向 (2015)
  • Author(s): 齋藤秀之
  • Organizer: 日本薬剤学会第30年会
  • Place of Presentation: 長崎
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] 腎線維化に対する新規慢性炎症制御因子CYLD機能低下の臨床的意義の解明 (2014)
  • Author(s): 米田剛、末永尚輝、薮内希、西一彦、齋藤秀之、城野博史
  • Organizer: 第31回日本薬学会九州支部大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-12-06 – 2014-12-07
• [Presentation] 虚血性急性腎障害ラットにおけるインドキシル硫酸産生阻害の腎保護効果 (2014)
  • Author(s): 小山直子、西郷智香、佐潟雅隆、野村結衣、松永里香、城野博史、西一彦、齋藤秀之
  • Organizer: 第67回日本薬理学会西南部会
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-23
• [Presentation] Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury (AKI) by suppressing indoxyl sulfate (IS) production and restoring renal organic anion transporters (2014)
  • Author(s): Yoneda G, Nomura Y, Saigo C, Yamamoto Y, Jono H, Saito H
  • Organizer: ・2014 American Society of Nephrology Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] ワークショップ1・尿毒素から見たCKDの病態と治療「肝硫酸転移酵素SULTを標的とするインドキシル硫酸産生阻害薬の腎保護作用と機序解明 (2014)
  • Author(s): 齋藤秀之、西一彦
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-07-03 – 2014-07-05
  • Invited
• [Presentation] 硫酸転移酵素（SULT）阻害薬によるインドキシル硫酸（IS）蓄積抑制と急性腎障害低減効果の検証 (2014)
  • Author(s): 野村祐依、西郷智香、佐潟雅隆、松永里香、城野博史、西一彦、齋藤秀之
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-07-03 – 2014-07-05
• [Presentation] Hepatic sulfotransferase (SULT) as a potential target for amelioration of ischemic acute kidney injury (AKI) by suppressing indoxyl sulfate accumulation (2014)
  • Author(s): Saito H, Saigo C, Yoshimura M, Komori M, Yamamoto Y, Nomura Y, Sagata M, Matsunaga R, Nishi K, Jono H
  • Organizer: 第8回国際尿毒症学会
  • Place of Presentation: 沖縄コンベンションセンター
• [Presentation] 虚血再灌流急性腎障害に伴うNrf2活性化にインドキシル硫酸蓄積が関与する (2013)
  • Author(s): 佐潟雅隆、吉村美里、脇田紋佳、西郷智香、山本悠子、米田剛、中馬江里奈、野村祐衣、松下裕子、西一彦、城野博史、齋藤秀之
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Involvement of Indoxyl sulfate (IS) in downregulation of pulmonary aquaporin (AQP)-5 in rats caused by bilateral nephrectomy (BNx)-induced acute kidney injury (AKI) (2013)
  • Author(s): Sagata M, Saigo C, Yoneda G, Yamamoto Y, Nomura Y, Nishi K, Jono H, Saito H.
  • Organizer: アメリカ腎臓学会第４６回年会
  • Place of Presentation: ジョージア国際会議場（アトランタ）
• [Presentation] 虚血再灌流急性腎障害ラットにおけるインドキシル硫酸産生阻害薬物の腎保護効果 (2013)
  • Author(s): 西郷智香、佐潟雅隆、野村祐依、松永里香、西一彦、齋藤秀之
  • Organizer: 第34回日本臨床薬理学会学術総会
  • Place of Presentation: 東京国際フォーラム
• [Book] 月刊「細胞」Topics from special edition (2016)
  • Author(s): 齋藤秀之
  • Total Pages: 55
  • Publisher: 南山堂
• [Book] Annual Review腎臓2016 (2015)
  • Author(s): 齋藤秀之
  • Total Pages: 206
  • Publisher: 中外医学社
• [Book] 月刊薬事：薬剤性腎障害のとらえ方「尿毒症物質の臨床薬理」 (2013)
  • Author(s): 齋藤秀之
  • Total Pages: 186
  • Publisher: じほう
• [Remarks] 熊本大学医学部附属病院薬剤部・臨床薬物動態学分野研究業績
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/default.html
• [Remarks] 熊本大学医学部附属病院薬剤部研究業績等
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/division/results.html