The analysis and identification of bome marrow drived liver repair cell

• Project/Area Number: 15K09005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Yamaguchi University
• Principal Investigator: YAMAMOTO Naoki 山口大学, 大学教育機構, 准教授 (90448283)
• Co-Investigator(Kenkyū-buntansha): 藤澤 浩一 山口大学, 大学院医学系研究科, 助教 (00448284) ; 高見 太郎 山口大学, 大学院医学系研究科, 講師 (60511251) ; 松本 俊彦 山口大学, 大学院医学系研究科, 助教 (70634723)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 再生医療 / 電子顕微鏡 / 骨髄細胞 / 幹細胞 / 免疫電顕 / 肝線維化 / GFP/CCl4モデル / MMP9 / 肝硬変 / 培養骨髄細胞 / EpCAM / 骨髄幹細胞 / 肝臓再生 / 肝線維化抑制

Outline of Final Research Achievements

We analyzed the characterization of the infused GFP-postive BMC using both EM and Immuno EM(IEM).We analyzed the image of IEM, comparing with the character of positive cells by immunohistochemistry and fluorescence staining(Antibody:GFP,MMP9, hepatoblastmarker-Liv2,CD44,A6,EpCAM,CXCR4,transcription regulator-maternal of inhibitor of differentiation-Maid).
We had two kinds of GFP positive BMCs.One group of GFP positive BMCs(MMP9 positive cells,CXCR4 positive cells)were similar to hepatocyte in size and located around fiber.These cells were round forms and had the increase of lysosome structure in cytoplasm and located on fiber in hepatic cord and repaired fibrosis. The other group cells(A6 positive cells, Liv2 positive cells, EpCAM positive cells) were small size and located in destructive area.These cells had high N/C ratio and smaller than hepatocyte and migrated into damaged cell area and had the phagocytic capacity. We detected that CXCR4 positive BMCs repaird liver fibrosis.

Research Products

• [Journal Article] Profiling of the circadian metabolome in thioacetamide-induced liver cirrhosis in mice. (2017)
  • Author(s): Fujisawa K, Takami T, Matsumoto T, Yamamoto N, Sakaida I.
  • Journal Title: Hepatol Commun. Volume: 1(7) Issue: 7 Pages: 704-718
  • DOI: 10.1002/hep4.1075
  • Peer Reviewed / Open Access
• [Journal Article] A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells. (2017)
  • Author(s): Matsuda T, Takami T, Sasaki R, Nishimura T, Aibe Y, Paredes BD, Quintanilha LF, Matsumoto T, Ishikawa T, Yamamoto N, Tani K, Terai S, Taura Y, Sakaida I.
  • Journal Title: Hepatology Communications Volume: 1 Issue: 7 Pages: 691-703
  • DOI: 10.1002/hep4.1071
  • Peer Reviewed / Open Access
• [Journal Article] Evaluating effects of L-carnitine on human bone-marrow-derived mesenchymal stem cells. (2017)
  • Author(s): Fujisawa K, Takami T (Corresponding), Fukui Y, Quintanilha LF, Matsumoto T, Yamamoto N, Sakaida I.
  • Journal Title: Cell Tissue Res Volume: 368(2) Issue: 2 Pages: 301-310
  • DOI: 10.1007/s00441-017-2569-0
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness of tolvaptan monotherapy and low-dose furosemide/tolvaptan combination therapy for hepatoprotection and diuresis in a rat cirrhotic model (2017)
  • Author(s): Tanabe N, Takami T, Fujisawa K, Matsumoto T, Yamamoto N, Sakaida I.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 61 Issue: 1 Pages: 53-59
  • DOI: 10.3164/jcbn.16-122
  • NAID: 130006847656
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of the effects of L-carnitine on medaka (Oryzias latipes) fatty liver. (2017)
  • Author(s): Fujisawa K, Takami T, Matsuzaki A, Matsumoto T, Yamamoto N, Terai S, Sakaida I.
  • Journal Title: Sci Rep. Volume: 7(1) Issue: 1 Pages: 2749-2749
  • DOI: 10.1038/s41598-017-02924-5
  • Peer Reviewed / Open Access
• [Journal Article] Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma. (2016)
  • Author(s): Yamamoto N, Saeki I, Yamasaki T, Takami T, Maeda M, Fujisawa K, Iwamoto T, Matsumoto T, Hidaka I, Ishikawa T, Uchida K, Tani K, Sakaida I.
  • Journal Title: World J Gastroenterol. Volume: 22(40) Pages: 8967-8977
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo. (2016)
  • Author(s): Harima H, Kaino S, Takami T, Shinoda S, Matsumoto T, Fujisawa K, Yamamoto N, Yamasaki T, Sakaida I.
  • Journal Title: BMC Cancer. Volume: 16 Issue: 1 Pages: 702-702
  • DOI: 10.1186/s12885-016-2744-9
  • Peer Reviewed / Open Access
• [Journal Article] Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib (2016)
  • Author(s): Yamamoto N, Yamasaki T, Takami T, Uchida K, Fujisawa K, Matsumoto T, Saeki I, Terai S, Sakaida I.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 58 Issue: 3 Pages: 202-209
  • DOI: 10.3164/jcbn.15-127
  • NAID: 130005149374
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [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] Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib (2016)
  • Author(s): Yamamoto N, Yamasaki T,Takami T,Matsumoto T,Fujisawa K,Saeki I,Uchida K, Terai S, Sakaida I,
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: in press
  • NAID: 130005149374
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Circadian variations in the liver metabolites of medaka (Oryzias latipes). (2015)
  • Author(s): Fujisawa K, Takami T, Kimoto Y, Matsumoto T, Yamamoto N, Terai S, Sakaida I.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 20916-20916
  • DOI: 10.1038/srep20916
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging. (2015)
  • Author(s): Fujisawa K, Terai S, Matsumoto T, Takami T, Yamamoto N, Nishina H, Furutani-Seiki M, Sakaida I.
  • Journal Title: PLoS One Volume: 10（６） Issue: 6 Pages: e0129950-e0129950
  • DOI: 10.1371/journal.pone.0129950
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A new therapeutic assessment score for advanced hepatocellular carcinoma patients receiving hepatic arterial infusion chemotherapy. (2015)
  • Author(s): Saeki I, Yamasaki T, Tanabe N, Iwamoto T, Matsumoto T, Urata Y, Hidaka I, Ishikawa T, Takami T, Yamamoto N, Uchida K, Terai S, Sakaida I.
  • Journal Title: PLoS One. Volume: 10(5) Issue: 5 Pages: e0126649-e0126649
  • DOI: 10.1371/journal.pone.0126649
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enhanced survival of mice infused with bone marrow-derived as compared with adipose-derived mesenchymal stem cells. (2014)
  • Author(s): Shiratsuki S, Terai S, Murata Y, Takami T, Yamamoto N, Fujisawa K, Burganova G, Quintanilha LF, Sakaida I.
  • Journal Title: Hepatol Res Volume: - Issue: 13 Pages: 1353-1359
  • DOI: 10.1111/hepr.12507
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 肝硬変症に対する自己骨髄細胞を用いた再生療法 (2017)
  • Author(s): 高見 太郎 松本 俊彦 藤澤 浩一 山本 直樹 坂井田 功
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台国際センター(宮城県・仙台市)
  • Year and Date: 2017-03-07
• [Presentation] Infused bone marrow derived cells have two capacities that repair of fibrosis and phagocytosis of damaged cells (2017)
  • Author(s): Naoki Yamamoto,Taro Takami, Shuji Terai, Koichi Uchida, Koichi Fujisawa, Toshihiko Matsumoto, Hiroshi Nishina,Isao Sakaida.
  • Organizer: The 14th Annual Meeting of the International Society for Stem Cell Research(ISSCR) Boston
  • Int'l Joint Research
• [Presentation] Nonclinical proof-of-concept for "hepatic artery infusion of cultured autologous bone marrow mesenchymal stem cells" in a canine liver fibrosis model (2017)
  • Author(s): Tatsuro Nishimura, Taro Takami, Ryo Sasaki, Yuki Aibe, Takashi Matsuda, Toshihiko, Matsumoto, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida
  • Organizer: The Liver Meeting 2017, AASLD Washington DC
  • Int'l Joint Research
• [Presentation] マクロファージRho family GTPaseを標的とした肝線維溶解療法に向けた基盤研究 (2017)
  • Author(s): 松本 俊彦、仁志 麻衣子、藤澤 浩一、高見 太郎、山本 直樹、坂井田 功
  • Organizer: 第53回日本肝臓学会総会 広島
• [Presentation] BCAA製剤によるSorafenibの治療効果増強と副作用軽減作用の解析 (2017)
  • Author(s): 山本 直樹、高見 太郎、藤澤 浩一、松本 俊彦、内田 耕一、坂井田 功
  • Organizer: 第53回日本肝臓学会総会 広島
• [Presentation] 骨髄間葉系幹細胞によるマクロファージMMP発現の制御 (2017)
  • Author(s): 仁志 麻衣子、松本 俊彦、藤澤 浩一、高見 太郎、山本 直樹、坂井田 功
  • Organizer: 第53回日本肝臓学会総会 広島
• [Presentation] イヌ線維化評価モデルによる培養自己骨髄間葉系幹細胞肝動脈投与の非臨床Proof of Conceptの取得 (2017)
  • Author(s): 西村 達朗、高見 太郎、佐々木 嶺、相部 祐希、松田 崇史、山本 直樹、坂井田 功
  • Organizer: 第53回日本肝臓学会総会 広島
• [Presentation] Rho family GTPases regulate MMPs expression and pro-inflammatory phenotype of macrophages in fibrotic liver. (2016)
  • Author(s): Toshihiko Matsumoto, Maiko Nishi, Koichi Fujisawa, Taro Takami, Naoki Yamamoto, Isao Sakaida
  • Organizer: The Liver Meeting 2016, AASLD
  • Place of Presentation: Boston USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Cultured bone marrow-derived mesenchymal stem cells contributed to improving liver cirrhosis through both the direct stabilization of redox homeostasis and cell-cell interaction with macrophages (2016)
  • Author(s): Taro Takami, Toshihiko Matsumoto, Maiko Nishi, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida
  • Organizer: The Liver Meeting 2016, AASLD
  • Place of Presentation: Boston USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] The efficacy and safety of liver regeneration therapy by hepatic arterial infusion of cultured autologous bone marrow mesenchymal stem cells in our established canine cirrhotic model (2016)
  • Author(s): Yuki Aibe, Taro Takami, Ryo Sasaki, Tatsuro Nishimura, Takashi Matsuda, Toshihiko Matsumoto, Koichi Fujisawa, Tsuyoshi Ishikawa, Naoki Yamamoto, Kenji Tani, Yasuho Taura, Isao Sakaida
  • Organizer: The Liver Meeting 2016, AASLD
  • Place of Presentation: Boston USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] 肝硬変症に対する自己骨髄細胞を用いた肝臓再生療法 (2016)
  • Author(s): 高見 太郎 松本 俊彦 山本 直樹 藤澤 浩一 坂井田 功
  • Organizer: JDDW 2016
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2016-11-03
• [Presentation] Infused bone marrow derived cells have two capacities that repair of fibrosis and phagocytosis of damaged cells (2016)
  • Author(s): Naoki Yamamoto,Taro Takami, Toshihiko Matsumoto, Koichi Uchida, Koichi Fujisawa, Isao Sakaida
  • Organizer: International Society for Stem Cell Research 2016 (ISSCR2016)
  • Place of Presentation: San Francisco USA
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Arterial infusion of cultured autologous bone marrow mesenchymal stem cells has a stronger therapeutic effect on liver cirrhosis in our established canine model (2016)
  • Author(s): Taro Takami, Yuki Aibe, Tatsuro Nishimura, Takashi Matsuda, Toshihiko Matsumoto, Koichi Fujisawa, Naoki Yamamoto, Kenji Tani, Yasuho Taura, Isao Sakaida
  • Organizer: International Society for Stem Cell Research 2016 (ISSCR2016)
  • Place of Presentation: San Francisco USA
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] イヌ肝線維化モデル系における培養自己骨髄間葉系幹細胞投与の有効性評価 (2016)
  • Author(s): 相部 祐希、高見 太郎、西村 達朗、佐々木 嶺、松田 崇史、藤澤 浩一、松本俊彦、石川 剛、山本 直樹、坂井田 功
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張
  • Year and Date: 2016-05-19
• [Presentation] 進行肝細胞癌に対する経口鉄キレート剤の治療戦略 (2016)
  • Author(s): 佐伯 一成、山本 直樹、高見太郎、山﨑隆弘、坂井田 功
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張(千葉県・千葉市)
  • Year and Date: 2016-05-19
• [Presentation] 肝硬変症に対する新規SGLT2(Sodium-Glucose Co-Transporter2)阻害剤の治療効果の基礎的検証と機序解明 (2016)
  • Author(s): 山本 直樹、高見 太郎、藤澤 浩一、松本俊彦、坂井田 功
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張(千葉県・千葉市)
  • Year and Date: 2016-05-19
• [Presentation] レボカルニチンによるSASP現象抑制効果によるNAFLD治療の可能性 (2016)
  • Author(s): 山本 直樹、高見 太郎、藤澤 浩一、松本俊彦、坂井田 功
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張(千葉県・千葉市)
  • Year and Date: 2016-05-19
• [Presentation] 肝臓再生療法における骨髄由来肝臓修復細胞の特徴 (2016)
  • Author(s): 山本 直樹
  • 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] L-carnitine prevents liver fibrosis and preneoplastic lesions in rat liver cirrhosis model induced by a choline-deficient L-amino acid-defined diet(CDAA) and Diethylnitrosamine (DEN) (2015)
  • Author(s): Naoki Yamamoto
  • Organizer: The 23th United European Gastroenterology Week (UEGW 2015)
  • Place of Presentation: Barcelona Convention Center (Spain)
  • Year and Date: 2015-10-24
  • Int'l Joint Research
• [Presentation] Infused bone marrow derived cells have two capacities that phagocytosis of damaged cells and repair of fibrosis in mice (2015)
  • Author(s): Naoki Yamamoto
  • Organizer: The 12th Annual Meeting of the International Society for Stem Cell Research (ISSCR) 2015
  • Place of Presentation: Stockholm convention center (Sweden)
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] 新規SGLT2(Sodium-Glucose Co-Transporter2)阻害剤の肝線維化抑制効果の基礎的検討 (2015)
  • Author(s): 山本 直樹
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本ホテル日航（熊本県・熊本市）
  • Year and Date: 2015-05-21
• [Presentation] レボカルニチンによるNAFLD治療効果の基礎的検討 (2015)
  • Author(s): 山本 直樹
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本ホテル日航（熊本県・熊本市）
  • Year and Date: 2015-05-21
• [Remarks]
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