Translational research for clinical apply using liver stem cells from cell banking

• Project/Area Number: 17K10672
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Sapporo Medical University
• Principal Investigator: MIZUGUCHI TORU 札幌医科大学, 保健医療学部, 教授 (30347174)
• Co-Investigator(Kenkyū-buntansha): 谷水 直樹 札幌医科大学, 医学部, 准教授 (00333386) ; 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, 助教 (50643201) ; 市戸 義久 札幌医科大学, 医学部, 助教 (80452978)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝細胞移植 / 細胞バンク / 肝切除 / 手術 / 肝幹細胞 / 細胞外基質 / ラミニン / インテグリン / 小型肝細胞 / 幹細胞移植 / 肝細胞 / 細胞採取 / 感染管理 / 細胞機能 / 細胞移植 / 肝再生 / 再生置換 / 幹細胞 / 外科 / 再生医学 / 再生医療 / 移植 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We established a method to identify and separate liver stem cells from CD45-, TER119-, CD31-, EpCAM-negative, and ICAM-1-positive cells as donor cells for hepatocyte-transplantation. From this cell population, cloned liver stem cells were established. Besides, donor cells treated with oncostatin M had improved regeneration replacement efficiency.　　Twenty-five studies targeting liver volume assessment were collected and reviewed to improve donor collection efficiency. When projected on a three-dimensional scatter plot as a standard liver volume calculation method, it was found that it was classified into two clusters.
The involvement of the structural variant of laminin could be on the self-renewal performance of the parental progenitor cells. When hyaluronic acid was used as a substrate, CD44-positive small hepatocytes proliferated, and the cell recovery rate and the retransplantation rate were improved under the conditions using Matrigel as a substrate.

Academic Significance and Societal Importance of the Research Achievements

ドナー細胞の抗原同定によって移植細胞源を最小限にし、再生効率を向上したことは学術的意義のみならず実用化に向けて大きな意義を持つ。安定した細胞源の確保と再生置換効率の向上は双方を兼ね備える必要がある。細胞採取時の画像評価法としてこれまで様々なものが考案されてきた。クラスター解析によって2群に分類されることを明らかにしたことは、多くの研究が固有の仮説と理論に従って報告してきたと思われるが、多くが同じものを検証していたにすぎないことが判明したことは社会的意義が大きい。ドナー細胞の改善のみならず増殖環境の細胞外基質との関連を明らかにした意義は大きい。

Research Products

• [Int'l Joint Research] アルバータ大学/膵島細胞移植機関/金 達也(カナダ)
• [Journal Article] Self-renewal capability of hepatocytic parental progenitor cells derived from adult rat liver Is maintained long term when cultured on laminin 111 in serum-free medium (2020)
  • Author(s): Kino J, Ichinohe N, Ishii M, Suzuki H, Mizuguchi T, Tanimizu N, Mitaka T
  • Journal Title: Hepatology Communications Volume: 4 Issue: 1 Pages: 21-37
  • DOI: 10.1002/hep4.1442
  • Peer Reviewed / Open Access
• [Journal Article] Scoring criteria for determining the safety of liver resection for malignant liver tumors (2019)
  • Author(s): Harada K, Nagayama M, Ohashi Y, Chiba A, Numazawa K, Meguro M, Kimura Y, Yamaguchi H, Kobayashi M, Miyanishi K, Kato J, Mizuguchi T
  • Journal Title: World Journal of Meta-Analysis Volume: 7 Issue: 5 Pages: 234-248
  • DOI: 10.13105/wjma.v7.i5.234
  • Peer Reviewed / Open Access
• [Journal Article] Quality assessment using Brief Cancer-Related Worry Inventory before and after gynecologic surgery for women. (2019)
  • Author(s): Kikuchi A, Koide R, Iwasaki M, Teramoto M, Satohisa S, Tamate M, Sawada I, Shudo E, Niwa N, Saito T, Mizuguchi T.
  • Journal Title: World J Obstet Gynecol Volume: 8 Issue: 1 Pages: 1-7
  • DOI: 10.5317/wjog.v8.i1.1
  • Peer Reviewed / Open Access
• [Journal Article] Quality assessment using EQ-5D-5L after lung surgery for non-small cell lung cancer (NSCLC) patients. (2019)
  • Author(s): Koide R, Kikuchi A, Miyajima M, Mishina T, Takahashi Y, Okawa M, Sawada I, Nakajima J, Watanabe A, Mizuguchi T.
  • Journal Title: Gen Thorac Cardiovasc Surg Volume: 67 Issue: 12 Pages: 1056-1061
  • DOI: 10.1007/s11748-019-01136-0
  • Peer Reviewed / Open Access
• [Journal Article] Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma. (2019)
  • Author(s): Shima H, Tsurita G, Wada S, Hirohashi Y, Yasui H, Hayashi H, Miyakoshi T, Watanabe K, Murai A, Asanuma H, Tokita S, Kubo T, Nakatsugawa M, Kanaseki T, Tsukahara T, Nakae Y, Sugita O, Ito YM, Ota Y, Kimura Y, Kutomi G, Hirata K, Mizuguchi T, Imai K, Takemasa I, Sato N, Torigoe T.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 8 Pages: 2378-2385
  • DOI: 10.1111/cas.14106
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series. (2019)
  • Author(s): Kubo T, Tsurita G, Hirohashi Y, Yasui H, Ota Y, Watanabe K, Murai A, Matsuo K, Asanuma H, Shima H, Wada S, Nakatsugawa M, Kanaseki T, Tsukahara T, Mizuguchi T, Hirata K, Takemasa I, Imai K, Sato N, Torigoe T.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 8 Pages: 2386-2395
  • DOI: 10.1111/cas.14099
  • Peer Reviewed / Open Access
• [Journal Article] Current status of projects for developing cancer-related clinical practice guidelines in Japan and recommendations for the future (2018)
  • Author(s): Imamura Masafumi,Hirata Koichi,Unno Michiaki,Kamiya Kinj,Gotoh Mitsukazu,Konno Hiroyuki,Shibata Akiko,Sugihara Kenichi,Takahashi Arata,Nishiyama Masahiko,Hakamada Kenichi,Fukui Tsuguya,Furukawa Toshiharu,Mizushima Tsunekazu,Mizuma Masamichi,Miyata Hiroaki,Mori Masaki,Takemasa Ichiro,Mizuguchi Toru,Fujiwara Toshiyoshi
  • Journal Title: International Journal of Clinical Oncology Volume: 24 Issue: 2 Pages: 189-195
  • DOI: 10.1007/s10147-018-1340-1
  • Peer Reviewed / Open Access
• [Journal Article] The Efficacy of Antimicrobial-Coated Sutures for Preventing Incisional Surgical Site Infections in Digestive Surgery: a Systematic Review and Meta-analysis. (2018)
  • Author(s): Uchino M, Mizuguchi T, Ohge H, Haji S, Shimizu J, Mohri Y, Yamashita C, Kitagawa Y, Suzuki K, Kobayashi M, Kobayashi M, Sakamoto F, Yoshida M, Mayumi T, Hirata K; SSI Prevention Guideline Committee of the Japan Society for Surgical Infection.
  • Journal Title: J Gastrointest Surg. Volume: 22 Issue: 10 Pages: 1832-1841
  • DOI: 10.1007/s11605-018-3832-8
  • Peer Reviewed
• [Journal Article] Long-term survival of a pancreatic cancer patient immunized with an SVN-2B peptide vaccine. (2018)
  • Author(s): Shima H, Kutomi G, Satomi F, Imamura M, Kimura Y, Mizuguchi T, Watanabe K, Takahashi A, Murai A, Tsukahara T, Kanaseki T, Hirohashi Y, Iwayama Y, Tsuruma T, Kameshima H, Sato N, Torigoe T, Takemasa I.
  • Journal Title: Cancer Immunol Immunother. Volume: 67 Issue: 10 Pages: 1603-1609
  • DOI: 10.1007/s00262-018-2217-x
  • Peer Reviewed
• [Journal Article] Antimicrobial susceptibility of common pathogens isolated from postoperative intra-abdominal infections in Japan (2018)
  • Author(s): Takesue Yoshio、Matsuo Yoichi、et.al
  • Journal Title: J Infect Chemother Volume: 24 Issue: 5 Pages: 330-340
  • DOI: 10.1016/j.jiac.2018.02.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway. (2017)
  • Author(s): Ogawa T, Hirohashi Y, Murai A, Nishidate T, Okita K, Wang L, Ikehara Y, Satoyoshi T, Usui A, Kubo T, Nakastugawa M, Kanaseki T, Tsukahara T, Kutomi G, Furuhata T, Hirata K, Sato N, Mizuguchi T, Takemasa I, Torigoe T.
  • Journal Title: Oncotarget Volume: 8 Issue: 68 Pages: 112550-112564
  • DOI: 10.18632/oncotarget.22545
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocytic parental progenitor cells of rat small hepatocytes maintain a self-renewal capability after long-term culture. (2017)
  • Author(s): Ishii M, Kino J, Ichinohe N, Tanimizu N, Ninomiya T, Suzuki H, Mizuguchi T, Hirata K, Mitaka T.
  • Journal Title: Scientific Reports, Volume: 7 Issue: 1 Pages: 46177-46177
  • DOI: 10.1038/srep46177
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antimicrobial susceptibility of pathogens isolated from surgical site infections in Japan: Comparison of data from nationwide surveillance studies conducted in 2010 and 2014?2015 (2017)
  • Author(s): Takesue Yoshio、Matsuo Yoichi、et al.
  • Journal Title: J Infect Chemother Volume: 23 Issue: 6 Pages: 339-348
  • DOI: 10.1016/j.jiac.2017.03.010
  • Peer Reviewed / 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
• [Presentation] Perioperative Infection Control and Management during Gastroenterological Surgery (2019)
  • Author(s): Toru Mizuguchi, Toshihiko Mayumi Hiroki Ohge, Masahiro Yoshida Motoi Uchino, Zyunzo Shimizu Seiji Haji, Yasuhiko Mouri Minoru Nagayama, Ichiro Takemasa
  • Organizer: 日本消化器外科学会
• [Presentation] 腹部外科手術にドレーンは必要か？ (2019)
  • Author(s): 水口徹、他
  • Organizer: 日本外科感染症学会
• [Presentation] 再肝切除症例に対する腹腔鏡下肝切除術の検討. (2018)
  • Author(s): 永山 稔, 木村 康利, 山口 洋志, 藤野 紘貴, 吉田 瑛司, 水口 徹, 他
  • Organizer: 第31回日本内視鏡外科学会.
• [Presentation] 腹腔鏡下肝切除術におけるICG蛍光法を用いた術中ナビゲーションに関する検討. (2018)
  • Author(s): 永山 稔, 木村 康利, 今村 将史, 山口 洋志, 吉田 瑛司, 藤野 紘貴, 水口 徹, 他
  • Organizer: 第80回日本臨床外科学会.
• [Presentation] 手術の安全性向上のために 肝予備能評価の現状. (2018)
  • Author(s): 水口 徹, 永山 稔, 山口 洋志, 藤野 紘貴, 吉田 瑛司, 今村 将史, 木村 康利, 他
  • Organizer: 第80回日本臨床外科学会.
• [Presentation] 腹腔鏡下肝切除術における罠と修繕. (2018)
  • Author(s): 水口 徹, 永山 稔, 山口 洋志, 今村 将史, 沖田 憲司, 西舘 敏彦, 伊東 竜哉, 信岡 隆幸, 木村 康利, 他
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] 周術期感染管理におけるSSI予防を目指すwound careの課題点. (2018)
  • Author(s): 水口 徹, 永山 稔, 山口 洋志, 今村 将史, 沖田 憲司, 西舘 敏彦, 木村 康利, 他
  • Organizer: 第118回日本外科学会定期学術集会.
• [Presentation] Validation of Harada score for the assessment of liver function; Is it possible to predict it preciously? (2017)
  • Author(s): Mizuguchi T, Nagayama M、Imamura M、Yamaguchi H、Nobuoka T、Nishidate T、Okita K、Ito T、Kimura Y、Takemasa I.
  • Organizer: The 6th Biennial Congress of the Asian-PacificHepato-Pancreato-Biliary Association The 29th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
• [Presentation] Clinical value of the ATIII as of liver functional indicator and prediction of surgical stress using difficulty score for pure laparoscopic liver resection (2017)
  • Author(s): Mizuguchi T, Nagayama M, Yamaguchi H, Imamura M, Okita K, Hishidate T, Ito T, Nobuoka T, Kimura Y, Takemasa I.
  • Organizer: The 72nd General Meeting of the Japanese Society of Gastroenterological Surgery