The Origin of Collagen-producing Myofibroblasts in Pancreatic Fibrosis

• Project/Area Number: 25670575
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: TAURA Kojiro 京都大学, 医学(系)研究科(研究院), 講師 (80378629)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 慢性膵炎 / 膵線維化 / 膵星細胞 / 肝星細胞 / ビタミンA / コラーゲン

Outline of Final Research Achievements

We aimed to pursue the origin of collagen-producing cells in pancreatic fibrosis by using transgenic mice expressing GFP under collagen α1(I) promoter. Pancreatic fibrosis was induced by cerulein. GFP-positive cells were seen along fibrotic septa but only a small minority of the cells were positive for glial fibrillary acidic protein (GFAP), a specific marker of PSCs.
The flowcytometry of isolated pancreatic cells from cerulein-treated mice showed GFAP-positive cells accounted for only 20% of GFP-positive cells. PSCs had lipid droplets, however, unlike HSCs, they lacked vitamin A autofluorescence. Liquid chromatography mass spectrometry analysis of the cell extract revealed PSCs contained only trace amounts of retinyl palmitate. The mRNA expression of Lrat, an enzyme necessary to esterify retinol, was much lower than that of HSCs. In conclusion, our study suggested the presence of collagen-producing cells other than PSCs and showed different characteristics between PSCs and HSCs.

Research Products

• [Journal Article] Strategies to Detect Hepatic Myofibroblasts in Liver Cirrhosis of Different Etiologies. (2014)
  • Author(s): Iwaisako K, Taura K, Koyama Y, Takemoto K, Asagiri M.
  • Journal Title: Curr Pathobiol Rep. Volume: 2 Pages: 209-215
  • Open Access
• [Journal Article] Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. (2014)
  • Author(s): Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, Toriguchi K, Tanabe K, Tanaka H, Seo S, Taura K, Machida K, Takeda N, Saji S, Uemoto S, Asagiri M.
  • Journal Title: FEBS Open Bio. Volume: 6 Issue: 2 Pages: 777-87
  • DOI: 10.1016/j.jss.2014.08.052
  • NAID: 120005496668
  • Peer Reviewed / Open Access
• [Journal Article] Hepatoprotective effect by pretreatment with olprinone in a swine partial hepatectomy model. (2014)
  • Author(s): Iguchi K, Hatano E, Yamanaka K, Sato M, Yamamoto G, Kasai Y, Okamoto T, Okuno M, Taura K, Fukumoto K, Ueno K, Uemoto S.
  • Journal Title: Liver Transpl. Volume: 20 Issue: 7 Pages: 838-49
  • DOI: 10.1002/lt.23884
  • NAID: 120005652823
  • Peer Reviewed
• [Journal Article] The impact of posthepatectomy liver failure on the recurrence of hepatocellular carcinoma (2014)
  • Author(s): Iguchi K, Hatano E, Yamanaka K, Tanaka S, Taura K, Uemoto S
  • Journal Title: World J Surg Volume: 38(1) Issue: 1 Pages: 150-158
  • DOI: 10.1007/s00268-013-2247-7
  • Peer Reviewed
• [Journal Article] Direct volume manipulation for visualizing intraoperative liver resection process (2014)
  • Author(s): Nakao M, Oda Y, Taura K, Minato K
  • Journal Title: Comput Methods Programs Biomed Volume: 113(3) Issue: 3 Pages: 725-735
  • DOI: 10.1016/j.cmpb.2013.12.004
  • NAID: 120005399110
  • Peer Reviewed
• [Journal Article] Effect of olprinone on liver microstructure in rat partial liver transplantation (2013)
  • Author(s): Yamanaka K, Hatano E, Iguchi K, Yamamoto G, Sato M, Toriguchi K, Tanabe K, Takemoto K, Nakamura K, Koyama N, Narita M, Nagata H, Taura K, Uemoto S
  • Journal Title: J Surg Res Volume: 183(1) Issue: 1 Pages: 391-396
  • DOI: 10.1016/j.jss.2012.11.033
  • NAID: 120005298136
  • Peer Reviewed
• [Journal Article] Effects of oral intake of hydrogen water on liver fibrogenesis in mice (2013)
  • Author(s): Koyama Y, Taura K, Hatano E, Tanabe K, Yamamoto G, Nakamura K, Yamanaka K, Kitamura K, Narita M, Nagata H, Yanagida A, Iida T, Iwaisako K, Fujinawa H, Uemoto S
  • Journal Title: Hepatol Res Volume: May 20 Issue: 6 Pages: 663-677
  • DOI: 10.1111/hepr.12165
  • Peer Reviewed
• [Journal Article] Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1 (2013)
  • Author(s): Nakamura K, Hatano E, Miyagawa-Hayashino A, Okuno M, Koyama Y, Narita M, Seo S, Taura K, Uemoto S
  • Journal Title: Liver Int Volume: Nov 29 Issue: 10 Pages: 1473-1487
  • DOI: 10.1111/liv.12420
  • Peer Reviewed
• [Presentation] 膵線維芽細胞起源の探求 (2015)
  • Author(s): 山本 玄, 田浦 康二朗, 田邉 和孝, 西尾 太宏 奥田 雄紀浩, 祝迫惠子, 波多野 悦朗, 上本 伸二
  • Organizer: 日本外科学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-16 – 2015-04-18
• [Presentation] 膵星細胞は脂肪滴にビタミンAを持たない (2014)
  • Author(s): 山本 玄, 田浦 康二朗, 小山 幸法, 田邉 和孝, 西尾 太宏 奥田 雄紀浩, 波多野 悦朗, 上本 伸二
  • Organizer: 日本外科学会総会総会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] Pancreatic Stellate Cells Do Not Have Vitamin A In Fat Droplets (2014)
  • Author(s): Yamamoto Gen
  • Organizer: Academic Surgical Congress
  • Place of Presentation: Manchester Grand Hyatt (San Diego, CA)
• [Presentation] 膵星細胞は脂肪滴にビタミンAを持たない (2014)
  • Author(s): 山本 玄
  • Organizer: 日本外科学会
  • Place of Presentation: 京都国際会館（京都市）
• [Presentation] Liver Stiffness Measurement Predicts Posthepatectomy Liver Failure (PHLF) (2014)
  • Author(s): Taura Kojiro
  • Organizer: Academic Surgical Congress
  • Place of Presentation: Manchester Grand Hyatt (San Diego, CA)
• [Presentation] 肝静脈根部大型肝癌に対する肝切除術式 (2014)
  • Author(s): 田浦康二朗
  • Organizer: 日本外科学会
  • Place of Presentation: 京都国際会館（京都市）