Cellular interaction in liver development and pathogenesis

• Project/Area Number: 22249011
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAJIMA Atsushi 東京大学, 分子細胞生物学研究所, 教授 (50135232)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Minoru 東京大学, 分子 細胞生物学研究所, 准教授 (80321909) ; ITOH Tohru 東京大学, 分子細胞 生物学研究所, 講師 (50396917) ; MIYAOKA Yuichiro 東京大学, 分子細胞生物学研究所, 助教 (20549521) ; SAIJOU Eiko 東京大学, 分子 細胞生物学研究所, 技術職員 (60376647)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥48,620,000 (Direct Cost: ¥37,400,000、Indirect Cost: ¥11,220,000); Fiscal Year 2012: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2011: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2010: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
• Keywords: 発生 / 再生 / 肝炎 / 線維化 / 細胞増殖 / サイトカイン / 細胞分裂 / 細胞肥大 / 細胞周期 / FGF / 幹細胞 / 肝障害 / ニッチ

Research Abstract

Liver is a unique organ with an extraordinary capacity to regenerate. This study showed importance of cellular hypertrophy of hepatocytes and proposes a revised model of liver regeneration after partial hepatectomy. Liver progenitor cells develop around the portal veins in some types of liver injuries, we found that FGF7 is essential for the induction of liver progenitors, and that they are important for the recovery from the liver injuries.

Research Products

• [Journal Article] Nephronectin is upregulated in acute and chronic hepatitis and aggravates liver injury by recruiting CD4 positive cells. (2013)
  • Author(s): Inagaki F., Tanaka M., Inagaki N., Yagai T.,Sato Y., Sekiguchi K., Oyaizu N., Kokudo N., and Miyajima A.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Pages: 751-756
  • Peer Reviewed
• [Journal Article] FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. (2013)
  • Author(s): Takase H., Itoh T., Wang T., Koji T., Akira S., Takikawa Y., and Miyajima A.
  • Journal Title: Genes and Development Volume: 27 Pages: 169-181
  • Peer Reviewed
• [Journal Article] Nephronectin is upregulated in acute and chronic hepatitis and aggravates liver injury by recruiting CD4 positive cells (2013)
  • Author(s): Inagaki F., Tanaka M., Inagaki N., Yagai T., Sato Y., Sekiguchi K., Oyaizu N., Kokudo N., and Miyajima A
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 430 Issue: 2 Pages: 751-756
  • DOI: 10.1016/j.bbrc.2012.11.076
  • Peer Reviewed
• [Journal Article] Inhibition of Stabilin-2 elevates the circulating hyaluronic acid level and prevents tumor metastasis. (2012)
  • Author(s): Hirose Y., Saijou E., Sugano Y., Takeshita F., Nishimura S., Nonaka H., Chen Y.-R., Sekine K., Kido T., Nakamura T., Kato S., Kanke T., Nakamura K., Nagai R., Ochiya T. and Miyajima A.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 109 Pages: 4263-4268
  • Peer Reviewed
• [Journal Article] Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. (2012)
  • Author(s): Miyaoka Y., Ebato K., Kato H., Arakawa S., Shimizu S., and Miyajima A.
  • Journal Title: Current Biology Volume: 22 Pages: 1166-1175
  • Peer Reviewed
• [Journal Article] Grainyhead-like 2 regulates epithelial morphogenesis by establishing functional tight junctions through the organization of a molecular network among claudin3, claudin4, and Rab25. (2012)
  • Author(s): Senga K., Mostov K. E., Mitaka T., Miyajima A., and Tanimizu N.
  • Journal Title: Mol Biol. Cell. Volume: 23 Pages: 2845-2855
  • Peer Reviewed
• [Journal Article] 1-and?5-Containing laminins regulate the development of bile ducts via?1-integrin signals. (2012)
  • Author(s): Tanimizu N., Kikkawa Y., Mitaka T. and Miyajima A. ?
  • Journal Title: J. Biol. Chem.
  • Peer Reviewed
• [Journal Article] Grainyhead-like 2 regulates epithelial morphogenesis by establishing functional tight junctions through the organization of a molecular network among claudin3, claudin4, and Rab25. (2012)
  • Author(s): Senga K., Mostov K. E., Mitaka T., Miyajima A., and Tanimizu N.
  • Journal Title: Mol Biol. Cell Volume: 23 Issue: 15 Pages: 2845-2855
  • DOI: 10.1091/mbc.e12-02-0097
  • Peer Reviewed
• [Journal Article] α1- and α5-Containing laminins regulate the development of bile ducts via β1-integrin signals. (2012)
  • Author(s): Tanimizu N., Kikkawa Y., Mitaka T. and Miyajima A.
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 34 Pages: 28586-28597
  • DOI: 10.1074/jbc.m112.350488
  • Peer Reviewed
• [Journal Article] Liver stem/progenitor cells: Their characteristics and regulatory mechanisms. (2011)
  • Author(s): Tanaka M., Itoh T., Tanimizu N. and Miyajima A.
  • Journal Title: J. Biochem. Volume: 149 Pages: 231-239
  • NAID: 10030583627
  • Peer Reviewed
• [Journal Article] Retention in the Golgi apparatus and expression on the cell surface of Cfr/Esl-1/Glg-1/MG-160 are regulated by two distinct mechanisms. (2011)
  • Author(s): Miyaoka Y., Kato H., Ebato K., Saito S., Miyata N., Imamura T., and Miyajima A.
  • Journal Title: Biochemical Journal. Volume: 44 Pages: 33-41
  • Peer Reviewed
• [Journal Article] TROP2 expressed in the trunk of the ureteric duct regulates branching morphogenesis during kidney development. (2011)
  • Author(s): Tsukahara Y., Tanaka M. and Miyajima A.
  • Journal Title: PLoS One Volume: 6
  • Peer Reviewed
• [Journal Article] IkBh, a nuclear IkB protein, positively regulates the NF-kB-mediated expression of pro-inflammatory cytokines. (2011)
  • Author(s): Yamauchi S, Ito H、, Miyajima A
  • Journal Title: Proc.Natl.Acad.Sci.USA. Volume: 107 Pages: 11924-11929
  • Peer Reviewed
• [Journal Article] A novel regulatory mechanism for FGF18 signaling involving cysteine-rich FGF receptor (Cfr) and Delta-like protein (Dlk). (2010)
  • Author(s): Miyaoka Y., Tanaka M., Imamura T., Takada S. and Miyajima A.
  • Journal Title: Development 137 Pages: 159-167
  • Peer Reviewed
• [Journal Article] Characterization and functional analyses of hepatic mesothelial cells in mouse liver development. (2010)
  • Author(s): Onitsuka I., Tanaka M., and Miyajima A.
  • Journal Title: Gastroenterology Volume: 138 Pages: 1525-1536
  • NAID: 40017376757
  • Peer Reviewed
• [Journal Article] I?B?, a nuclear I?B protein, positively regulates the NF-?B-mediated expression of pro-inflammatory cytokines. (2010)
  • Author(s): Yamauchi S., Ito H., and Miyajima A.
  • Journal Title: Natl. Acad. Sci. USA Volume: 107 Pages: 11924-11929
  • Peer Reviewed
• [Journal Article] Dlk-1, a cell surface antigen on hepatic stem/progenitor cells, is expressed in hepatocellular, colon, pancreas and breast carcinomas at a high frequency. (2010)
  • Author(s): Yanai H., Nakura K., Hijioka S., Kamei A., Ikari T., Ishikawa,Y., Shinozaki E., Mizunuma N., Hatake K., and Miyajima A.
  • Journal Title: J.Biochem Volume: 148 Pages: 85-92
  • Peer Reviewed
• [Journal Article] Dlk-1, a cell surface antigen on hepatic stem/progenitor cells, is expressed in hepatocellular, colon, pancreas and breast carcinomas at a high frequency (2010)
  • Author(s): Yanai H, Nakura K, Hijioka S, Kamei A, Ikari T, Ishikawa, Y, Shinozaki E, Mizunuma N., Hatake K, Miyajima A
  • Journal Title: J.Biochem. Volume: 148 Pages: 85-92
  • Peer Reviewed
• [Journal Article] Liver stem/progenitor cells : Their characteristics and regulatory mechanisms (2010)
  • Author(s): Tanaka M, Itoh T, TanimizuN, Miyajima A
  • Journal Title: J.Biochem Volume: 149 Pages: 231-239
  • NAID: 10030583627
  • Peer Reviewed
• [Presentation] FGF7 is a functional niche signal required for stimulation of adult liver (2013)
  • Author(s): Tohru Itoh, Hinako Takase, Atsushi Miyajima
  • Organizer: Keystone Symposia on Molecular and Cellular Biology, "Stem Cell Regulation in Homeostasis and Disease"
  • Place of Presentation: Banff, Canada
• [Presentation] FGF7 is a functional niche signal required for stimulation of adult liver (2013)
  • Author(s): Tohru Itoh, Hinako Takase, Atsushi Miyajima
  • Organizer: Keystone Symposia on Molecular and Cellular Biology, "Stem Cell Regulation in Homeostasis and Disease"
  • Place of Presentation: Banff (Canada)
• [Presentation] Critical role of FGF7 for development of adult liver stem/progenitor cells and regeneration in damaged livers (2012)
  • Author(s): Tohru Itoh, Hinako Takase, Atsushi Miyajima
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Colorad (USA)
• [Presentation] Cellular basis for liver regeneration (2012)
  • Author(s): A. Miyajima
  • Organizer: Liver Metabolism, Diseases and Cancer
  • Place of Presentation: Suzhou (China)
  • Invited
• [Presentation] Role for stem/progenitor cells in liver regeneration (2012)
  • Author(s): A. Miyajima
  • Organizer: First EHBH International Forum on Liver Biomarkers
  • Place of Presentation: Shanghai (China)
  • Invited
• [Presentation] オンコスタチンMはマクロファージのM1/M2バランスに作用しインスリン抵抗性を改善する (2012)
  • Author(s): 田中稔、小森 忠祐、森川吉博、仙波恵美子、宮島篤
  • Organizer: 第85回 日本生化学会
  • Place of Presentation: 福岡
• [Presentation] 肝再生および肝線維化におけるSemaphorin 3Eの機能 (2012)
  • Author(s): 谷貝 知樹、田中 稔、宮島 篤
  • Organizer: 第85回生化学会大会
  • Place of Presentation: 福岡
• [Presentation] 肝臓の発生および代謝機能獲得におけるTribbles遺伝子の役割 (2012)
  • Author(s): 西條 栄子, 内木 隆, 宮島 篤
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] オンコスタチンMによる骨髄造血環境の制御機構の解明 (2012)
  • Author(s): 佐藤 郁、田中 稔、宮島 篤
  • Organizer: 第85回 日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] A novel 3D imaging technique reveals dynamic behavior of the biliary tree in regenerating livers (2012)
  • Author(s): 金子 洸太、伊藤 暢、宮島 篤
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Critical role of FGF7 for development of adult liver stem/progenitor cells and regeneration in damaged livers (2012)
  • Author(s): Tohru Itoh, Hinako Takase, Atsushi Miyajima
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Colorado (USA)
• [Presentation] 肝臓の発生および代謝機能獲得におけるTribbles遺伝子の役割 (2012)
  • Author(s): 西條 栄子, 内木 隆, 宮島 篤
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡
• [Presentation] FGF7 is critical for progenitor cell-mediated regeneration in the adultmouse liver (2011)
  • Author(s): Itoh T, Takase H, MiyajimaA
  • Organizer: Keystone Symposia on Molecular and Cellular Biology "Stem Cells in Development, Tissue Homeostasis and Disease"
  • Place of Presentation: Eldorado Hotel & Spa, Santa Fe, New Mexico, USA
  • Year and Date: 2011-01-31
• [Presentation] Liver stem/progenitor cells in normal and pathological conditions (2010)
  • Author(s): Tanaka M, Itoh T, Takase H, Onitsuka I, Tsukahara Y, HiroseY, Kamiya Y, Miyajima A
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Snowmass Village Conference Center CO USA
• [Presentation] Searching for signaling molecules regulating adult liver progenitor cell response using the hydrodynamic tail vein injection-mediated in vivogene transfer technique (2010)
  • Author(s): Itoh T, Takase H, MiyajimaA.
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Snowmass Village Conference Center CO USA
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝炎モデル非ヒ ト哺乳動物及びその作製方法 (2012)
  • Inventor(s): 宮島篤、田中稔
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 2012-144737
  • Filing Date: 2012-06-28
  • Overseas
• [Patent(Industrial Property Rights)] オンコスタチンM受容体シグナリン グ制御によるメタボリック症候群の治療 (2011)
  • Inventor(s): 森川吉博、宮島篤、田中稔、小森 忠祐
  • Industrial Property Rights Holder: 和歌山県立医科大学,東京大学
  • Industrial Property Number: 2011-208354
  • Filing Date: 2011-09-26
  • Overseas
• [Patent(Industrial Property Rights)] NAFLD の進展度合いを判定する方法 (2010)
  • Inventor(s): 寺井崇二、大石俊之、坂井田功、 桑代紳哉、宮島篤
  • Industrial Property Rights Holder: 山口大学,東京大学
  • Filing Date: 2010-06-04
  • Overseas