Cellular interaction in liver inflammation and regeneration

• Project/Area Number: 26253023
• 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 国立国際医療研究センター, 室長 (80321909) ; ITOH Tohru 東京大学, 分子細胞生物学研究所, 准教授 (50396917) ; ENOMOTO Yutaka 東京大学, 分子細胞生物学研究所, 助教 (20608210) ; KIDO Taketomo 東京大学, 分子細胞生物学研究所, 助教 (00401034) ; SAIJOU Eiko 東京大学, 分子細胞生物学研究所, 技術専門員 (60376647)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥40,820,000 (Direct Cost: ¥31,400,000、Indirect Cost: ¥9,420,000); Fiscal Year 2016: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2015: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2014: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
• Keywords: 炎症 / 再生 / 線維化 / サイトカイン / イメージング / 肝炎 / 胆管 / 肝臓 / 肝障害 / 肝細胞 / 間葉系細胞 / 幹細胞 / 免疫

Outline of Final Research Achievements

This study was aimed at elucidating the cellular basis of liver inflammation and regeneration. Ductular reaction in chronic liver injuries is characterized by amplification of duct like cells. We developed novel methods for imaging and cell fact tracking to reveal the mode of remodeling of bile ducts. Proliferating duct cells were found to be localized at the periphery of the ducts and their fate was stochastically determined. We found that expression of Oncostatin M in the liver induces fibrosis without inflammation and using this system we revealed cellular interactions among liver cells, which lead to fibrosis. Over expression of IL-4 in the liver induces a distinct class of NK cells that possess strong cytotoxic activity against tumor cells.

Research Products

• [Journal Article] Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree. (2017)
  • Author(s): Yagai T, Matsui S, Harada K, Inagaki FF, Saijou E, Miura Y, Nakanuma Y, Miyajima A, *Tanaka M.
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: e0175355-e0175355
  • DOI: 10.1371/journal.pone.0175355
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Portal fibroblasts marked by the surface antigen Thy1 contribute to pathogenesis of liver fibrosis in mouse models of cholestatic liver injury (2017)
  • Author(s): Katsumata L, Miyajima A, and Itoh T
  • Journal Title: Hepatology Communications Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intrahepatic bile ducts are developed through formation of homogeneous continuous liminal network and its dynamic rearrangement. (2016)
  • Author(s): Tanimizu N, Kaneko K, Itoh T, Ichinohe N, Ishii M, Mizuguchi T, Hirata K, Miyajima A, Mitaka T.
  • Journal Title: Hepatology Volume: in press Issue: 1 Pages: 175-188
  • DOI: 10.1002/hep.28521
  • Peer Reviewed
• [Journal Article] NK cells activated by Interleukin-4 in cooperation with Interleukin-15 exhibit distinctive characteristics. (2016)
  • Author(s): Kiniwa T, Enomoto Y, Omi A, Miyata N, Ishiwata K and Miyajima A
  • Journal Title: Proc. Nat. Acad. SCi. USA. Volume: 113 Issue: 36 Pages: 10139-10144
  • DOI: 10.1073/pnas.1600112113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling (2016)
  • Author(s): Kenji Kamimoto, Kota Kaneko, Cindy Yuet-Yin Kok, Hajime Okada, Atsushi Miyajima, Tohru Itoh
  • Journal Title: eLife Volume: 5
  • DOI: 10.7554/elife.15034
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Liver regeneration and fibrosis after inflammation (2016)
  • Author(s): Tanaka M and Miyajima A.
  • Journal Title: Miyajima A. Liver regeneration and fibrosis after inflammation. Volume: 36 Issue: 1 Pages: 19-19
  • DOI: 10.1186/s41232-016-0025-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Adaptive Remodeling of the Biliary Architecture Underlies Liver Homeostasis (2015)
  • Author(s): 金子 洸太、神元 健児、宮島 篤、伊藤 暢
  • Journal Title: Hepatology Volume: 未定 Issue: 6 Pages: 2015-2015
  • DOI: 10.1002/hep.27685
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cell-based therapy for preventing postoperative adhesion and promoting regeneration after hepatectomy. (2015)
  • Author(s): Inagaki NF, Inagaki FF, Kokudo N, Miyajima A
  • Journal Title: Journal of Hepato-Billiary-Pancreatic Sciences Volume: 印刷中 Issue: 7 Pages: 524-530
  • DOI: 10.1002/jhbp.247
  • Peer Reviewed
• [Journal Article] Adaptive remodelling of the biliary tree: the essence of liver progenitor cell expansion (2015)
  • Author(s): Cindy Yuet-Yin Kok, Atsushi Miyajima, and Tohru Itoh
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 未定 Issue: 7 Pages: 546-550
  • DOI: 10.1002/jhbp.250
  • Peer Reviewed
• [Journal Article] 1. CPM is a useful cell surface marker to isolate expandable bi-potential liver progenitor cells derived from human iPS cells. (2015)
  • Author(s): Kido T, Koui Y, Suzuki K, Kobayashi A, Miura Y, Chen EY, Tanaka M, Miyajima A.
  • Journal Title: Stem Cell Reports Volume: 5 Issue: 4 Pages: 508-515
  • DOI: 10.1016/j.stemcr.2015.08.008
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 2. Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice. (2015)
  • Author(s): Komori T, Tanaka M, Furuta H, Akamizu T, Miyajima A, Morikawa Y
  • Journal Title: Diabetologia Volume: 58 Issue: 8 Pages: 1868-1876
  • DOI: 10.1007/s00125-015-3613-9
  • Peer Reviewed
• [Journal Article] Use of mouse liver mesothelial cells to prevent postoperative adhesion and promote liver regeneration after hepatectomy. (2015)
  • Author(s): Inagaki NF, Inagaki FF, Kokudo N, Miyajima A
  • Journal Title: Journal of hepatology Volume: 62 Issue: 5 Pages: 1141-7
  • DOI: 10.1016/j.jhep.2014.12.010
  • Peer Reviewed
• [Journal Article] Semaphorin 3E secreted by damaged hepatocytes regulates the sinusoidal regeneration and liver fibrosis during liver regeneration. (2014)
  • Author(s): Yagai T, Miyajima A, Tanaka M
  • Journal Title: American Journal of Pathology Volume: 184 Issue: 8 Pages: 2250-2259
  • DOI: 10.1016/j.ajpath.2014.04.018
  • Peer Reviewed
• [Journal Article] Mature resting Ly6Chigh natural killer cells can be reactivated by IL-15. (2014)
  • Author(s): Omi A, Enomoto Y, Kiniwa T, Miyata N and Miyajima A.
  • Journal Title: Eur. J. Immunology. Sep Volume: 44(9) Issue: 9 Pages: 2638-47
  • DOI: 10.1002/eji.201444570
  • Peer Reviewed
• [Presentation] Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling (2016)
  • Author(s): Kamimoto K, Kaneko K, Kok CY, Itoh T, Miyajima A
  • Organizer: Frontiers 2016 Symposium
  • Place of Presentation: ローザンヌ（スイス）
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Presentation] Oncostatin M plays a crucial role in liver fibrogenesis by regulating cooperation between hepatic stellate cells and macrophages (2016)
  • Author(s): Michitaka Matsuda, Atsushi Miyajima, Minoru Tanaka
  • Organizer: AASLD The liver meeting 2016
  • Place of Presentation: Boston（U.S.A）
  • Year and Date: 2016-11-14
  • Int'l Joint Research
• [Presentation] Mechanism of Liver Regeneration (2016)
  • Author(s): Atsushi Miyajima
  • Organizer: 2016 Taiwan Digestive Disease Week
  • Place of Presentation: Taipei（Taiwan）
  • Year and Date: 2016-09-30
  • Int'l Joint Research / Invited
• [Presentation] TROP2を指標とした胆道系幹/前駆細胞 (BTSC)の同定 (2016)
  • Author(s): 松井 理司、宮島 篤、田中 稔
  • Organizer: 第89回 日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 非アルコール性脂肪性肝炎の病態形成における多様な細胞死の意義 (2016)
  • Author(s): 鶴崎慎也, 松田道隆, 清水重臣, 中野裕康, 宮島篤, 田中稔
  • Organizer: 第89回 日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 好中球の肝線維化改善効果 (2016)
  • Author(s): 西條栄子、榎本豊、松田道隆、シンディコック、田中稔、宮島篤
  • Organizer: 第23回肝細胞研究会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-07-08
• [Presentation] Intra-vital imaging of bile flow reveals a new role of ductular reaction in liver regeneration (2016)
  • Author(s): Kenji Kamimoto, Kota Kaneko, Atsushi Miyajima, Tohru Itoh
  • Organizer: FASEB Science Research Conference, Liver Biology: Fundamental Mechanisms and Translational Applications
  • Place of Presentation: Marriott West Palm Beach（USA）
  • Year and Date: 2016-06-28
  • Int'l Joint Research
• [Presentation] Remodeling of the Biliary Tree During Liver Regeneration (2016)
  • Author(s): Atsushi Miyajima, Kenji Kamimoto, Kota Kaneko and Tohru Itoh
  • Organizer: Cold Spring Harbor Asia: Liver diseases and turmorigenesis
  • Place of Presentation: Suzhou（China）
  • Year and Date: 2016-04-25
  • Int'l Joint Research / Invited
• [Presentation] ヒトiPS細胞由来CPM陽性肝前駆細胞からの成熟肝細胞の誘導 (2016)
  • Author(s): 木戸 丈友、厚井 悠太、小林 彩香、大山 裕棋、 田中 稔、宮島 篤
  • Organizer: 第１５回 日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-03-17
• [Presentation] Stochastic conversion of the growth mode of biliary epithelial cells controls tissue remodeling in regenerating mouse liver (2016)
  • Author(s): Kenji Kamimoto, Kota Kaneko, Tohru Itoh, Atsushi Miyajima
  • Organizer: Keystone symposia 2016, Stem Cells and Regeneration in Digestive Organs
  • Place of Presentation: Keystone Colorado（ USA）
  • Year and Date: 2016-03-13
  • Int'l Joint Research
• [Presentation] Stochastic conversion of the growth mode of biliary epithelial cells controls tissue remodeling in regenerating mouse liver (2016)
  • Author(s): Kenji Kamimoto, Kota Kaneko, Tohru Itoh, Atsushi Miyajima
  • Organizer: Keystone symposia 2016, Stem Cells and Regeneration in Digestive Organs
  • Place of Presentation: Keystone, Colorado (U.S.A.)
  • Year and Date: 2016-03-13
  • Int'l Joint Research
• [Presentation] 代償性肝再生における肝中皮細胞の増殖と肥大 (2015)
  • Author(s): 野上亮佑 稲垣奈都子 宮島篤
  • Organizer: 第38回日本分子生物学会年会,第88回日本生化学会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-03
• [Presentation] Lutheranは肝幹／前駆細胞の性状を制御する機能性マーカー分子である (2015)
  • Author(s): 三浦泰史、田中稔、吉川大和、合田亘人、宮島篤
  • 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: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] マウス肝外胆管からのBiliary Tree Stem/Progenitor Cell（BTSC）の単離・同定とその性状解析 (2015)
  • Author(s): 松井理司 田中稔 宮島篤
  • 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: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Cellular Basis of Liver Regeneration (2015)
  • Author(s): Atsushi Miyajima
  • Organizer: 2015 International Conference on Stem Cells and Developmental Biology
  • Place of Presentation: Taipei（Taiwan）
  • Year and Date: 2015-10-16
  • Int'l Joint Research / Invited
• [Presentation] Cellular Basis of Liver Regeneration (2015)
  • Author(s): 宮島篤
  • Organizer: 2015 International Conference on Stem Cells and Developmental Biology
  • Place of Presentation: Taipei (Taiwan)
  • Year and Date: 2015-10-16
  • Int'l Joint Research / Invited
• [Presentation] 肝切除後癒着に対するiPS細胞を用いた癒着防止療法の検討 (2015)
  • Author(s): 稲垣奈都子 稲垣冬樹 國土典宏 宮島篤
  • Organizer: 日本消化器関連学会週間JDDW 2015
  • Place of Presentation: グランドプリンスホテル新高輪 （東京都港区）
  • Year and Date: 2015-10-08
• [Presentation] 肝臓の再生メカニズム (2015)
  • Author(s): 宮島篤
  • Organizer: 第６回Molecular Cardiovascular Conference II
  • Place of Presentation: ヒルトンホテル（福岡県福岡市）
  • Year and Date: 2015-09-04
  • Invited
• [Presentation] 肝臓の発生・再生における肝前駆細胞 (2015)
  • Author(s): 宮島篤
  • Organizer: 第３９回阿蘇シンポジウム
  • Place of Presentation: 阿蘇リゾート グランヴィリオホテル（熊本県阿蘇市）
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] 肝臓の発生・再生における肝前駆細胞 (2015)
  • Author(s): 宮島篤
  • Organizer: 第３９回阿蘇シンポジウム
  • Place of Presentation: 阿蘇リゾートグランヴィリオホテル（熊本県阿蘇市）
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] 肝臓の炎症と再生 (2015)
  • Author(s): 宮島篤
  • Organizer: 第３６回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（ 東京都港区）
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] 肝再生のメカニズム (2015)
  • Author(s): 宮島篤
  • Organizer: 第８０回日本インターフェロン・サイトカイン学会
  • Place of Presentation: 東京工業大学蔵前会館(東京都目黒区）
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] Identification of mouse Biliary Tree Stem/Progenitor Cell (BTSC) based on TROP2 expression profile. (2015)
  • Author(s): 松井理司 田中稔 宮島篤
  • Organizer: 第13回 幹細胞シンポジウム
  • Place of Presentation: 伊藤国際学術研究センター (東京都文京区）
  • Year and Date: 2015-05-29
• [Presentation] Mechanism of liver fibrosis induced by Oncostatin M (2015)
  • Author(s): 松田道隆、田中稔、宮島篤
  • Organizer: 第５１回日本肝臓学会総会
  • Place of Presentation: 熊本ホテルキャッスル（熊本県熊本市）
  • Year and Date: 2015-05-22
• [Presentation] Interleukin 4 induces a unique NK cell population in vivo and in vitro (2015)
  • Author(s): Kiniwa T, Enomoto Y, Omi A, Miyajima A
  • Organizer: IMMUNOLOGY 2015 AAI Annual Meeting
  • Place of Presentation: New Orleans（ USA）
  • Year and Date: 2015-05-11
  • Int'l Joint Research
• [Presentation] Interleukin 4 induces a unique NK cell population in vivo and in vitro (2015)
  • Author(s): Kiniwa T, Enomoto Y, Omi A, Miyajima A
  • Organizer: IMMUNOLOGY 2015 AAI Annual Meeting
  • Place of Presentation: New Orleans (U.S.A.)
  • Year and Date: 2015-05-11
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来肝前駆細胞の二分化能の解析 (2015)
  • Author(s): 木戸丈友、厚井悠太、田中稔、小林彩香、宮島篤
  • Organizer: 第14回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-03-19
• [Presentation] Overexpression of IL-4 augments NK cell activities in vivo (2014)
  • Author(s): 木庭乾、榎本豊、尾見歩惟、宮島篤
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-12-10
• [Presentation] Role of M2-like macrophages in liver fibrosis (2014)
  • Author(s): 西條栄子、松田道隆、榎本豊、田中稔、宮島篤
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館・グランドプリンスホテル京都（京都府京都市）
  • Year and Date: 2014-10-18
• [Presentation] Novel visualization method reveals connection of adult liver progenitor cells to biliary trees in various liver injuries (2014)
  • Author(s): Kota Kaneko, Tohru Itoh, Atsushi Miyajima
  • Organizer: FASEB Summer Research Conferences / Liver Biology
  • Place of Presentation: Keystone, Colorado (U.S.A.)
  • Year and Date: 2014-07-08
  • Int'l Joint Research
• [Presentation] Notch signaling promotes proliferation of adult liver progenitor cells and progenitor-dependent liver regeneration (2014)
  • Author(s): Tohru Itoh, Seitaro Ino, and Atsushi Miyajima
  • Organizer: FASEB Summer Research Conferences / Liver Biology
  • Place of Presentation: Keystone, Colorado (U.S.A.)
  • Year and Date: 2014-07-08
  • Int'l Joint Research
• [Presentation] Mechanism of liver fibrosis induced by Oncostatin M (2014)
  • Author(s): 松田道隆、田中稔、宮島篤
  • Organizer: FASEB Summer Research Conferences / Liver Biology
  • Place of Presentation: Keystone, Colorado (U.S.A.)
  • Year and Date: 2014-07-06
  • Int'l Joint Research
• [Presentation] 肝臓の炎症・再生－基礎から応用へ (2014)
  • Author(s): 宮島篤
  • Organizer: 第35回 日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄県名護市）
  • Year and Date: 2014-07-03
  • Invited
• [Patent(Industrial Property Rights)] 肝細胞及び肝非実質細胞、並びにそれらの調製方法 (2016)
  • Inventor(s): 宮島篤、木戸丈友、厚井悠太、小林彩香
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-03-16
• [Patent(Industrial Property Rights)] 中皮細胞の製造方法、及び癒着防止用細胞シート (2015)
  • Inventor(s): 宮島篤、稲垣奈都子、稲垣冬樹、國土典広
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-24
• [Patent(Industrial Property Rights)] 中皮細胞を含む肝細胞増殖促進剤 (2015)
  • Inventor(s): 稲垣奈都子、宮島篤
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-07-28