Analysis of cellular quality control in liver tissue formation

• Project/Area Number: 26293012
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NISHINA Hiroshi 東京医科歯科大学, 難治疾患研究所, 教授 (60212122)
• Co-Investigator(Kenkyū-buntansha): 浅岡 洋一 東京医科歯科大学, 難治疾患研究所, 助教 (10436644)
• Co-Investigator(Renkei-kenkyūsha): HIRAYAMA Jun 東京医科歯科大学, 難治疾患研究所, 准教授 (90510363) ; MIYAMURA Norio 東京医科歯科大学, 難治疾患研究所, 助教 (10725493)
• Research Collaborator: KATADA Toshiaki 東京大学, 大学院薬学研究科, 教授 ; MIYAJIMA Atsushi 東京大学, 大学分子細胞生物学研究所, 教授
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 肝臓 / シグナル / ストレス / 器官形成 / 障害 / モザイク解析 / Hippo / YAP / 細胞排除 / モデル生物 / メダカ / 肝発生 / 肝再生 / シグナル伝達 / Hippoシグナル / 品質管理 / PDZ結合ドメイン / 細胞増殖 / 細胞分化

Outline of Final Research Achievements

The presence of senescent, transformed, or damaged cells can impair tissue function or lead to tumorigenesis. However, how this quality control is regulated remains largely unclear. Here, using in vivo mosaic analysis in mouse liver, we show that YAP activation induced by inactivation of the Hippo pathway specifically in damaged hepatocytes induces their selective elimination. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis, and are engulfed by Kupffer cells. This involves the activation of CDC42 and Rac to regulate cell migration. Thus, YAP acts as a stress sensor that induces the elimination of injured cells to maintain tissue and organ homeostasis.

Research Products

• [Int'l Joint Research] IMBA(オーストリア)
• [Journal Article] The mevalonate pathway regulates primitive streak formation via protein farnesylation (2016)
  • Author(s): Okamoto-Uchida Y, Yu R, Miyamura N, Arima N, Ishigami-Yuasa M, Kagechika H, Yoshida S, Hosoya T, Nawa M, Kasama T, Asaoka Y, Alois RW, Elling U, Penninger JM, Nishina S, Azuma N, Nishina H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37697-37697
  • DOI: 10.1038/srep37697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status. (2016)
  • Author(s): Chiba, T., Ishihara, E., Miyamura, N., Narumi, R., Kajita, M., Fujita, Y., Suzuki, A., Ogawa, Y. and *Nishina, H.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 28383-28383
  • DOI: 10.1038/srep28383
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SLC7 family transporters control the establishment of left-right asymmetry during organogenesis in medaka by activating mTOR signaling. (2016)
  • Author(s): Asaoka Y, Nagai Y, Namae M, Furutani-Seiki M, Nishina H
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 474 Issue: 1 Pages: 146-153
  • DOI: 10.1016/j.bbrc.2016.04.087
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetically Encoded Fluorescent Probe for Imaging Apoptosis in Vivo with Spontaneous GFP Complementation. (2016)
  • Author(s): Yusuke Nasu, Yoichi Asaoka, Misako Namae, Hiroshi Nishina, Hideaki Yoshimura and Takeaki Ozawa
  • Journal Title: Anal Chem Volume: 88 Issue: 1 Pages: 838-844
  • DOI: 10.1021/acs.analchem.5b03367
  • Peer Reviewed / Open Access
• [Journal Article] Validation of the chemical compound library screening for TAZ inhibitors by use of green fluorescence protein-fused TAZ. (2016)
  • Author(s): Nagashima S, Maruyama J, Kawano S, Iwasa H, Nakagawa K, Ishigami-Yuasa M, Kagechika H, Nishina H, Hata Y.
  • Journal Title: Cancer Sci. Volume: - Issue: 6 Pages: 791-802
  • DOI: 10.1111/cas.12936
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. (2016)
  • Author(s): Fujisawa K, Terai S, Takami T, Yamamoto N, Yamasaki T, Matsumoto T, Yamaguchi K, Owada Y, Nishina H, Noma T, Sakaida I.
  • Journal Title: J Exp Clin Cancer Res. Volume: - Issue: 1 Pages: 48-48
  • DOI: 10.1186/s13046-016-0322-2
  • NAID: 120006937642
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulated YAP1/TAZ and TGF signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice (2015)
  • Author(s): Nishio, M., Sugimachi, K., Goto, H., Wang, J., Morikawa, T., Miyachi, Y., Takano, Y., Hikasa, H., Itoh, T., Suzuki, S.O., Kurihara, H., Aishima, S., Leask, A., Sasaki, T., Nakano, T., Nishina, H., Nishikawa, Y., Sekido, Y., Nakao, K., Shin-ya, K., Mimori, K. and Suzuki, A.
  • Journal Title: PNAS Volume: 113 Issue: 1 Pages: 71-80
  • DOI: 10.1073/pnas.1517188113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis (2015)
  • Author(s): Ruoxing Yu, Norio Miyamura, Yoshimi Okamoto-Uchida, Norie Arima, Mari Ishigami-Yuasa, Hiroyuki Kagechika and Hiroshi Nishina
  • Journal Title: PLoS ONE Volume: 10 Issue: 12 Pages: e0145286-e0145286
  • DOI: 10.1371/journal.pone.0145286
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] YAP is essential for tissue tension to ensure vertebrate 3D body shape (2015)
  • Author(s): Sean Porazinski, Huijia Wang, Yoichi Asaoka, Martin Behrndt, Tatsuo Miyamoto, Hitoshi Morita, Shoji Hata et al.
  • Journal Title: Nature Volume: 印刷中 Issue: 7551 Pages: 217-221
  • DOI: 10.1038/nature14215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish (2014)
  • Author(s): Yoichi Asaoka, Shoji Hata, Misako Namae, Makoto Furutani-Seiki and Hiroshi Nishina
  • Journal Title: PLoS ONE Volume: 9 Issue: 5 Pages: e97365-e97365
  • DOI: 10.1371/journal.pone.0097365
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity. (2014)
  • Author(s): Shimomura T, Miyamura N, H ata S, Miura R, Hirayama J, N ishina H
  • Journal Title: Biochemical and Biophysical Research Communi cations Volume: 443 Issue: 3 Pages: 917-923
  • DOI: 10.1016/j.bbrc.2013.12.100
  • Peer Reviewed
• [Journal Article] Screening with a Novel Cell-Based Assay for TAZ Activators Identifies a Compound That Enhances Myogenesis in C2C12 Cells and Facilitates Muscle Repair in a Muscle Injury Model. (2014)
  • Author(s): Yang, Z. Y.; Nakagawa, K.; Sarkar, A.; Maruyama, J.; Iwasa, H.; Bao, Y. J.; Ishigami-Yuasa, M.; Ito, S.; Kagechika, H.; Hata, S.; Nishina, H.; Abe, S.; Kitagawa, M.; Hata, Y.
  • Journal Title: Mol. Cell. Biol. Volume: 34 Issue: 9 Pages: 1607-1621
  • DOI: 10.1128/mcb.01346-13
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of autotaxin, a lysophosphatidic acid-producing enzyme, enhances cardia bifida induced by hypo-sphingosine-1-phosphate signaling in zebrafish embryo (2014)
  • Author(s): Nakanaga K, Hama K, Kano K, Sato T, Yukiura H, Inoue A, Saigusa D, Tokuyama H, Tomioka Y, Nishina H, Kawahara A, Aoki J
  • Journal Title: J. Biochem Volume: 155 Issue: 4 Pages: 235
  • DOI: 10.1093/jb/mvt114
  • NAID: 40020035029
  • Peer Reviewed / Open Access
• [Journal Article] Status and prospects of liver cirrhosis treatment by using bone marrow-derived cells and mesenchymal cells. (2014)
  • Author(s): Terai S, Takami T, Yamamoto N, Fujisawa K, Ishikawa T, Urata Y, Tanimoto H, Iwamoto T, Mizunaga Y, Matsuda T, Oono T, Marumoto M, Burganova G, Fernando Quintanilha L, Hidaka I, Marumoto Y, Saeki I, Uchida K, Yamasaki T, Tani K, Taura Y, Fujii Y, Nishina H, Okita K, Sakaida I.
  • Journal Title: Tissue Eng Part B Rev Volume: 20(3) Issue: 3 Pages: 206-210
  • DOI: 10.1089/ten.teb.2013.0527
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 器官形成におけるHippo-YAPシグナル伝達経路の役割-幹細胞・前駆細胞の分化制御 (2016)
  • Author(s): 仁科博史
  • Organizer: 第89回日本生化学大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] 器官の３D構築とサイズの制御 (2016)
  • Author(s): 仁科博史
  • Organizer: 第7回Molecular Cardiovascular Conference
  • Place of Presentation: 東京
  • Year and Date: 2016-09-02
  • Invited
• [Presentation] メダカに学ぶ再生医療の基礎 (2016)
  • Author(s): 仁科博史
  • Organizer: 第15回公開市民講座
  • Place of Presentation: 東京都文京区
  • Invited
• [Presentation] ３D器官構築を制御するHippo-YAPシグナル伝達経路 (2015)
  • Author(s): 仁科博史
  • Organizer: 9th: Metabolic Research Cutting Edge
  • Place of Presentation: 第一三共本社（東京）
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] 脊椎動物3D器官形成を制御するHippo-YAPシグナル伝達経路 (2015)
  • Author(s): 仁科博史
  • Organizer: 日本Cell Death学会
  • Place of Presentation: 大阪大学（大阪）
  • Year and Date: 2015-07-11
  • Invited
• [Presentation] The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish (2015)
  • Author(s): Hiroshi Nishina
  • Organizer: 2015 Keystone Symposia The Hippo Pathway: Signaling, Development and Disease
  • Place of Presentation: New Mexico（米国）
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] がん原遺伝子産物YAP依存的肝細胞消失を誘導する新規マウスモデルの確立 (2014)
  • Author(s): 仁科博史
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜、パシフィコ
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] 成体マウス肝臓においてモザイク状のHippoシグナル伝達系破綻は細胞排除を誘導する (2014)
  • Author(s): 仁科博史
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都、国際会議場
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 器官サイズを制御する転写共役因子YAPの役割 (2014)
  • Author(s): 仁科博史
  • Organizer: 第23回日本Cell Death学会
  • Place of Presentation: 東京、東京医科歯科大学M&Dタワー
  • Year and Date: 2014-07-18 – 2014-07-19
  • Invited
• [Book] 発生・器官形成、がん悪性化に関わるHippoシグナル-創薬標的として高まるYAP/TAZへの期待 (2015)
  • Author(s): 仁科博史
  • Total Pages: 133
  • Publisher: 羊土社
• [Remarks] 「異常な細胞の除去を誘導する新たな仕組みの解明に成功」 ― がんの予防的治療法の開発に期待 ―
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20160621_2.pdf
• [Remarks] 発生初期の器官形成の鍵となる組織の分化に必要な代謝経路の解明
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20161124.pdf
• [Remarks] 東京医科歯科大学難治疾患研究所 発生再生生物学分野
  • URL: http://www.tmd.ac.jp/mri/dbio/index.html