Translational research of the regenerative treatment of using human hepatic stem cells which were frozen by super-freezing program

• Project/Area Number: 26461921
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Sapporo Medical University
• Principal Investigator: MIZUGUCHI TORU 札幌医科大学, 医学部, 准教授 (30347174)
• Co-Investigator(Kenkyū-buntansha): 谷水 直樹 札幌医科大学, 医学部, 准教授 (00333386) ; 平田 公一 札幌医科大学, 医学部, 教授 (50136959) ; 三高 俊広 札幌医科大学, 医学部, 教授 (50231618) ; 石井 雅之 札幌医科大学, 医学部, 研究員 (50643201) ; 市戸 義久 札幌医科大学, 医学部, 研究員 (80452978)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝再生 / 幹細胞 / 細胞バンク / 超過冷却 / 肝細胞移植 / 肝細胞 / 手術 / 腹腔鏡 / 肝不全 / 腹腔鏡下肝切除 / 肝細胞癌

Outline of Final Research Achievements

We aimed at establishing the cell harvest method for human hepatocyte with safety and technical issues. We reported an effective method for donor cell harvests with video presentation. We also elucidate clinical values of lactate levels during the cell harvesting. We developed a standard for evaluating postoperative complications. We investigate a cell harvest method regarding anatomical location of the donor cells. BCAA plays an important role to maintain nutritional balance. We also aimed at establishing a banking hepatic stem cells and investigate cell preparation and cell nature. In the research period, we success to separate and culture hepatic stem cells. We tried to protect the method by a patent. Finally, we found an antigen to identify hepatic stem cells and select specific cells for regenerative therapy.

Research Products

• [Int'l Joint Research] UCSF/Beioff's Children Hospital/Oakland(米国)
• [Int'l Joint Research]
• [Journal Article] Transplantation of Thy1+ cells accelerates liver regeneration by enhancing the growth of small hepatocyte-like progenitor cells via IL17RB signaling. (2017)
  • Author(s): Ichinohe N, Ishii M, Tanimizu N, Kon J, Mizuguchi T, Hirata K, Mitaka T.
  • Journal Title: Stem Cells Volume: 35(4) Issue: 4 Pages: 920-931
  • DOI: 10.1002/stem.2548
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Technical aspects and surgical complications of laparoscopic liver resection. (2017)
  • Author(s): Nagayama M, Mizuguchi T, Yamaguchi H, Imamura M, Kutomi G, Okita K, Nishidate T, Takemasa I, Kimura Y.
  • Journal Title: Ann Laparosc Endosc Surg Volume: 2 Pages: 61-61
  • DOI: 10.21037/ales.2017.02.25
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Liver progenitors isolated from adult healthy mouse liver efficiently differentiate to functional hepatocytes in vitro and repopulate liver tissue. (2016)
  • Author(s): Tanimizu N, Ichinohe N, Ishii M, Kino J, Mizuguchi T, Hirata K, Mitaka T.
  • Journal Title: Stem Cells Volume: 34(12) Issue: 12 Pages: 2889-2901
  • DOI: 10.1002/stem.2457
  • Peer Reviewed
• [Journal Article] Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer-Initiating Cells and Is a Potent Target of Immunotherapy (2016)
  • Author(s): Rena Morita, Yoshihiko Hirohashi, et al.
  • Journal Title: Clinical Cancer Research Volume: 1;22(13) Issue: 13 Pages: 3298-308
  • DOI: 10.1158/1078-0432.ccr-15-1709
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathological spectrum of bile duct lesions from chronic bile duct injury to invasice cholangiocarcinoma corresponding to bile duct imaging findings of occupational cholangiocarcinoma. (2016)
  • Author(s): Kinoshita M, Kubo S, Nakanuma Y, Sato Y, Takemura S, Tanaka S, Hamano G, Ito T, Terajima H, Yamada T, Nakamori S, Arimoto A, Fujikawa M, Sugawara Y, Yamamoto T, Abue M, Nakagawa K, Unno M, Mizuguchi T, Takenaka K, Shirabe K, Shibata T.
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: 23 Issue: 2 Pages: 92-101
  • DOI: 10.1002/jhbp.305
  • Peer Reviewed / 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] Pancreatic regeneration: basic research and gene regulation (2016)
  • Author(s): Okita K, Mizuguchi T*, Ota S, Ishii M, Nishidate T, Ueki T, Meguro M, Kimura Y, Tanimizu N, Ichinohe N, Torigoe T, Kojima T, Mitaka T, Sato N, Sawada N, and Hirata K
  • Journal Title: Surg Today Volume: 46 Issue: 6 Pages: 633-640
  • DOI: 10.1007/s00595-015-1215-2
  • Peer Reviewed
• [Journal Article] The impact of aging on morbidity and mortality after liver resection: a systematic review and meta-analysis (2015)
  • Author(s): Mizuguchi T, Kawamoto M, Meguro M, Okita K, Ota S, Ishii M, Ueki T, Nishidate T, Kimura Y, Furuhata T, Hirata K
  • Journal Title: Surgery Today Volume: 45 Issue: 3 Pages: 259-270
  • DOI: 10.1007/s00595-014-0863-y
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients. (2015)
  • Author(s): Meguro M, Mizuguchi T, Nishidate T, Okita K, Ishii M, Ota S, Ueki T, Akizuki E, Hirata K.
  • Journal Title: World J Gastroenterol. Volume: 21 Issue: 16 Pages: 4933-4945
  • DOI: 10.3748/wjg.v21.i16.4933
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical comparison of laparoscopic and open liver resection after propensity matching selection. (2015)
  • Author(s): Meguro M, Mizuguchi T, Kawamoto M, Ota S, Ishii M, Nishidate T, Okita K, Kimura Y, Hirata K.
  • Journal Title: Surgery. Volume: 158 Issue: 3 Pages: 573-587
  • DOI: 10.1016/j.surg.2015.02.031
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Preoperative liver function assessments to estimate the prognosis and safety of liver resections (2014)
  • Author(s): Mizuguchi T, Kawamoto M, Meguro M, Hui TT, Hirata K.
  • Journal Title: Surg Today Volume: 44 Issue: 1 Pages: 1-10
  • DOI: 10.1007/s00595-013-0534-4
  • Peer Reviewed / Open Access
• [Journal Article] Highest intraoperative lactate level could predict postoperative infectious complications after hepatectomy, reflecting the Pringle maneuver especially in chronic liver disease. (2014)
  • Author(s): Meguro M, Mizuguchi T, Kawamoto M, Nishidate T, Ishii M, Tatsumi H, Kimura Y, Furuhata T, Hirata K.
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: in press Issue: 7 Pages: 489-498
  • DOI: 10.1002/jhbp.87
  • Peer Reviewed / Open Access
• [Journal Article] Soluble lutheran/basal cell adhesion molecule is detectable in plasma of hepatocellular carcinoma patients and modulates cellular interaction with laminin-511 in vitro (2014)
  • Author(s): Kikkawa Y, Miwa T, Tanimizu N, Kadoya Y, Ogawa T, Katagiri F, Hozumi K, Nomizu M, Mizuguchi T, Hirata K, Mitaka T
  • Journal Title: Experimental Cell Research Volume: 328 Issue: 1 Pages: 197-206
  • DOI: 10.1016/j.yexcr.2014.07.012
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive review of post-liver resection surgical complications and a new universal classification and grading system (2014)
  • Author(s): Ishii M, Mizuguchi T, Harada K, Ota S, Meguro M, Ueki T, Nishidate T, Okita K, Hirata K
  • Journal Title: World Journal of Hepatology Volume: 27 Issue: 10 Pages: 745-751
  • DOI: 10.4254/wjh.v6.i10.745
  • Peer Reviewed / Open Access
• [Journal Article] Propensity score analysis demonstrated the prognostic advantage of anatomical liver resection in hepatocellular carcinoma. (2014)
  • Author(s): Ishii S, Mizuguchi T, Kawamoto M, Meguro M, Ota S, Nishidate T, Okita K, Kimura Y, Hui TT, Hirata K.
  • Journal Title: World J Gastroenterol. Volume: 20 Issue: 12 Pages: 3335-3342
  • DOI: 10.3748/wjg.v20.i12.3335
  • NAID: 40020253731
  • Peer Reviewed / Open Access
• [Journal Article] Saline injection method for facilitating the liver hanging maneuver during hepatectomy for a large right liver tumor. (2014)
  • Author(s): Mizuguchi T, Kawamoto M, Meguro M, Okita K, Nishidate T, Furuhata T, Hui TT, Hirata K.
  • Journal Title: J Am Col Surg Volume: 219 Issue: 2 Pages: e11-e14
  • DOI: 10.1016/j.jamcollsurg.2014.01.065
  • Peer Reviewed / Open Access
• [Journal Article] Left Lateral Sectionectomy Performed Under Minimal Open Access after the Completion of Hand-Assisted Laparoscopic Mobilization. (2013)
  • Author(s): Mizuguchi T, Kawamoto M, Meguro M, Ota S, Ishii S, Okita K, Kimura Y, Furuhata T, Hirata K.
  • Journal Title: J Liver Volume: ２ Issue: 5 Pages: 5-5
  • DOI: 10.4172/2167-0889.1000141
  • Peer Reviewed / Open Access
• [Presentation] 完全腹腔鏡下肝切除術の難易度スコアの変遷と術中出血対応 (2016)
  • Author(s): 水口 徹、目黒 誠、沖田 憲司、西舘 敏彦、今村 将史、山口 洋志、伊東 竜哉、河野 剛、信岡 隆幸、木村 康利、竹政伊知朗
  • Organizer: 第29回 日本内視鏡外科学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-08
• [Presentation] 周術期の真菌感染症との付き合い方 (2016)
  • Author(s): 水口 徹、目黒 誠、川本雅樹、沖田憲司、信岡隆幸、西舘敏彦、今村将史、伊東竜哉、木村康利、竹政伊知朗
  • Organizer: 第29回日本外科感染症学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-11-30
• [Presentation] 肝離断に関する現時点で考えられる理想的方法と工夫 (2016)
  • Author(s): 水口 徹、目黒 誠、今村将史、及能大輔、山口洋志、河野 剛、沖田憲司、西舘敏彦、木村康利、竹政伊知朗
  • Organizer: 第78回 日本臨床外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪 国際館パミール（東京都港区）
  • Year and Date: 2016-11-24
• [Presentation] Severe surgical complications after hepatectomy during the last decade. (2016)
  • Author(s): Mizuguchi T, Meguro M, Kawamoto M, Ota S, Okita K, Nishidate T, Imamura M, Nobuoka T, Ito T, Kimura Y, Takemasa I
  • Organizer: 第28回日本肝胆膵外科学会・学術集会
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2016-06-02
• [Presentation] An extracorponeal hepatic inflow control for pure laparoscopic liver resection can extend an indication of liver resection. (2016)
  • Author(s): 606Mizuguchi T, Meguro M, Okita K, Nishidate T, Ueki T, Akizuki E, Imamura M, Kutomi G, Kimura Y, Takemasa I.
  • Organizer: SAGES 2016 Surgical Spring Week
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-03-16
• [Presentation] 腹腔鏡下肝部分切除を究める経過中の報告 (2015)
  • Author(s): 水口 徹, 目黒 誠, 沖田 憲司, 西舘 敏彦, 植木 知身, 久能 大助, 信岡 隆幸, 伊東 竜哉, 木村 康利, 太田 盛道, 平田 公一, 古畑 智久
  • Organizer: 第28回日本内視鏡外科学会総会
  • Place of Presentation: 大阪国際会議場 （大阪市）
  • Year and Date: 2015-12-10
• [Presentation] 高齢者に対する肝切除術の治療成績 システマティクレヴューとメタ解析 (2015)
  • Author(s): 水口 徹, 目黒 誠, 沖田 憲司, 西舘 敏彦, 久能 大助, 植木 知身, 秋月 恵美, 信岡 隆幸, 今村 将史, 木村 康利, 平田 公一
  • Organizer: 第77回日本臨床外科学会総会
  • Place of Presentation: 福岡国際会議場 （福岡県福岡市）
  • Year and Date: 2015-11-26
• [Presentation] Front line in open and endoscopic liver surgery-perspective strategy and technique. (2015)
  • Author(s): Mizuguchi T, Meguro M, Nishidate T, Okita K, Imamura M, Nobuoka T, Kimura Y, Ito T, Furuhata T, Hirata K.
  • Organizer: 第27回日本肝胆膵外科学会・学術集会
  • Place of Presentation: ホテルグランパシフィックLE DAIBA (東京都港区)
  • Year and Date: 2015-06-11
• [Presentation] Clinical comparison of laparoscopic and open liver resection after propensity matching selection. (2015)
  • Author(s): Meguro M, Mizuguchi T, Kawamoto K, S. Ota, M. Ishii, Nishidate T, Okita K, Kimura Y, Hirata K.
  • Organizer: 10th Annual Academic Surgical Congress, Quick shot oral presentation
  • Place of Presentation: Las Vegas, NV, USA
  • Year and Date: 2015-02-03 – 2015-02-05
• [Presentation] Optimal Imaging Method of Preoperative 3DCT for Malignant Liver Tumors. (2014)
  • Author(s): Harada K, Honma S, Chiba A, Oohashi Y, Imai T, Hatakenaka M, Mizuguchi T, Hirata K.
  • Organizer: 100th Radiological Society of North America 2014
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-11-30 – 2014-12-05
• [Presentation] Vitamin A-Binding Liposome Containing Heat Shock Protein 47 siRNA Regulates Pancreatic Regeneration. (2014)
  • Author(s): Ota S, Mizuguchi T, Nishimura M, Ishi1 M, Okita K, Nishidate T, Nobuoka1 T, Kimura Y, Niitsu Y, Hirata K.
  • Organizer: 45th Anniversary Meeting of American Pancreatic Association and Japan Pancreas Society
  • Place of Presentation: Big Island, Hawaii, USA
  • Year and Date: 2014-11-05 – 2014-11-08
• [Presentation] The Clinical Implication of Repeat Pancreatectomy for Recurrent Pancreatic Cancer in the Remnant Pancreas after Initial Pancreatectomy (2014)
  • Author(s): Kyuno T, Kimura Y, Imamura M, Ito T, Nobuoka T, Mizuguchi T, Furuhata T, Hirata K.
  • Organizer: 45th Anniversary Meeting of American Pancreatic Association and Japan Pancreas Society
  • Place of Presentation: Big Island, Hawaii, USA
  • Year and Date: 2014-11-05 – 2014-11-08
• [Presentation] A novel technique of aqua-hanging maneuver method for large right liver tumors. (2014)
  • Author(s): Mizuguchi T, Hirata K, Meguo M, Ishii M, Okita K, Nishidate T, Ueki T, Ota S, Nobuoka T, Kimura Y, Kawamoto M.
  • Organizer: The Scientific Meeting of the Japan-Hungary-Poland Surgical Society Triangle Sympoisium 2014
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] 肝臓外科手術の低侵襲性を再考する―プロペンシティー解析も含めてのエビデンス― (2014)
  • Author(s): 水口 徹, 目黒 誠, 西舘 敏彦, 沖田 憲司, 植木 知身, 信岡隆幸、原田敬介、古畑智久、木村康利, 平 公一.
  • Organizer: 第27回日本内視鏡外科学会
  • Place of Presentation: 盛岡
  • Year and Date: 2014-10-02 – 2014-10-04
• [Presentation] 星細胞特異的DDSを用いた線維化溶解療法の臨床応用に向けた基礎研究. (2014)
  • Author(s): 太田盛道、水口 徹、木村康利、新津洋司郎、平田公一.
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-02 – 2014-04-04
• [Presentation] Clinical role of aldehyde dehydrogenase 1 expression in NBNC hepatocellular carcinoma patients after initial hepatectomy. (2014)
  • Author(s): 水口 徹、川本雅樹、目黒 誠、沖田憲司、西舘敏彦、植木知身、九冨五郎、信岡隆幸、木村康利、古畑智久、平田公一.
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-02 – 2014-04-04
• [Book] The branched chain amino acids in health and disease. (2015)
  • Author(s): Mizuguchi T, Mitaka T, Hirata K.
  • Total Pages: 333
  • Publisher: Springer
• [Patent(Industrial Property Rights)] 小型肝細胞の継代培養法 (2016)
  • Inventor(s): 三高俊広、石井雅之、市戸義久、谷水直樹、水口徹、平田公一.
  • Industrial Property Rights Holder: 三高俊広、石井雅之、市戸義久、谷水直樹、水口徹、平田公一.
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-016210
  • Filing Date: 2016-01-29