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Establishment of isolation procedure of human hepatic stem cell and tissue engineering technique to reconstitute hepatic tissue using the stem cell.

Research Project

Project/Area Number 11558101
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biomedical engineering/Biological material science
Research InstitutionAkita Univereity

Principal Investigator

SUGIYAMA Toshihiro  Akita University School of Medicine, Prof., 医学部, 教授 (00127242)

Co-Investigator(Kenkyū-buntansha) SAWAI Hiroshi  Akita Sumitomo Bakelite Co., Ltd. Scientist., 研究員
TERADA kunihiko  Akita University School of Medicine, Associate Prof., 医学部, 助教授 (60197796)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsStem cell / Cell transplantation / Collagen gel / Collagen sponge / Analbuminemic rat / Cell differentiation / Organ regeneration / 発生・分化 / 肝再生 / 細胞移植治療 / 星細胞 / 不死化肝細胞 / 肝細胞 / 胆管上皮細胞 / 組織再生工学 / 人工肝臓構築 / 肝臓幹様細胞 / 肝特異的転写因子 / HNF-1
Research Abstract

[Aim]ln this study, we first tried to establish the procedure for isolation ofhepatic stem cell from healthy human liver. Next, we examined whether the hepatic stem cell has potential to differentiate into hepatocyte, biliary epithelial cell, or pancreatic cell under tri-dimensional culture condition by using collagen gel developed by Akita Sumitomo Bakelite Co., Ltd. Finally, we aimed the clinical application of topo-organ reconstituted by the ex vivo transplantation of hepatic stem cell.
[Achievements]
(1)We have established a liver epithelial cell line, designated hepatic stem like (HSL) cell, from nonparenchymal fraction of healthy rat liver.
(2)The HSL cells are small with 20 μm in diameter and showed high nucleus/cytoplasm ratios. These cells expressed α-fetoprotein, but not albumin nor cytokeratin 19, indicating the cells have immature phenotype.
(3)We cultured the HSL cells in collagen gels or with hepatic stellate cells to investigate their potential to differentiate. Consequently, both of culture conditions induced the HSL cells to express albumin, showing that the HSL cells are able to differentiate into mature cells.
(4)Finally, we examined how we process the HSL cells to manifest the hepatic function in vivo. To this end, we transplanted the HSL cells which were mixed with collagen gel or embedded in collagen sponge into analbuminemic rats. As a result, analbuminemic rats that showed the increased levels of serum albumin were 67% in the rats transplanted the HSL cells with collagen gel and 57% in the rats with collagen sponge. This suggests that the transplanted HSL cells have differentiated into albumin producing cells and function as hepatocytes in vivo. The present study implies the possibility of clinical application of HSL cells.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (68 results)

All Other

All Publications (68 results)

  • [Publications] 寺田邦彦, 他: "肝幹細胞"Annual Review 消化器2002. 34-39 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanzaki A, et al.: "Copper-transporting P-Type Adenosine Triphosphatase (ATP7B) Is Expressed in Human Breast Carcinoma"Jpn. J. Cancer Res.. 93. 70-77 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kameda T, et al.: "Acceleration of the formation of cultured epithelium using the sonic hedgehog expressing feeder cells"Tissue Eng.. 7. 545-555 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "A Mutation of Wilson's Disease Protein, ATP7B, Is Degraded in the Proteasomes and Forms Protein Aggregates"Gastroenterology. 120. 967-974 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Demitsu T, et al.: "Hypertrichosis induced by latanoprost"J. Am. Acad. Dermatol. 44. 721-723 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ichihara T, et al.: "Resistance to fluminant hepatitis and carcinogenesis conferred by overexpression of retinoblastoma protein in mouse liver"Hepatology. 33. 948-955 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "肝幹細胞を利用した肝組織の再構成"医学のあゆみ. 196. 383-386 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "幹細胞を用いたミニ肝臓の形成"GI Research. 93. 70-77 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "幹細胞を用いたミニ肝臓の形成"Molecular Medicine. 38. 16-22 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "肝臓幹細胞とその分化"肝臓. 42. 389-397 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "Role of ATP7B in Biliary Copper Excretion in a Human Hepatoma Cell Line and Normal Rat Hepatocytes"Gastroenterology. 118. 921-928 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Komatsu M, et al.: "Copper transporting P-type adenosine triphosphatase (ATP7B) is associated with Cisplatin resistance"Cancer Res.. 60. 1312-1316 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita K, et al.: "Quantitative detection of apoptotic thymocytes in low-dose X-irradiated mice by an anti-single-stranded DNA antibody"J. Radiat. Res.. 41. 139-149 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "Copper does not alter the intracellular distribution of ATP7B, a copper-transporting ATPase"Biochem. Biophys. Res. Commun. 275. 871-876 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yang X.L., et al.: "MFH-1 is required for bone morphogenetic protein-2-induced osteoblastic differentiation of C2C12 myoblasts"FEBS Letters. 470. 29-34 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Narisawa T, et al.: "Inhibitory effects of ursodeoxycholic acid on N-methyl-nitrosourea-induced colon carcinogenesis and colonic mucosal telomerase activity in F344 rats"J. Exp. Clin. Cancer Res., 18 : 259-266, 1999. 18. 259-266 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Biliary expression of copper in LEC rat after introduction of copper transporting P-type ATPase, ATP7B"FEBS Lett.. 448. 53-56 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "The Long-Evans Cinnamon rat : An animal model for Wilson's disease"Pediatr. Int.. 41. 414-418 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sugiyama T, at al.: "Reconstitution of hepatic tissue using liver stem cells"Growth, proliferation, and apoptosis in hepatocytes (Okita K., ed.), Springer-Verlag, Tokyo. 100 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "組織工学的手法を利用したミニ肝臓の作製"消化器疾患の最新医療(森岡恭彦、他編).先端医療技術研究所.東京. 663 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "肝幹細胞と毛幹細胞"化学フロンティア(3)再生医工学(筏義人、編).化学同人.京都. 254 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Hepatic stem cell"Annual review of digestive disease in 2002. 34-39 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanzaki A, et al.: "Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma."Jpn. J. Cancer Res.. 93. 70-77 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kameda T, et al.: "Acceleration of the formation of cultured epithelium using the sonic hedgehog expressing feeder cells."Tissue Eng.. 7. 545-555 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "A mutation of Wilson's disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates."Gastroenterology. 120. 967-974 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Demitsu T, et al.: "Hypertrichosis induced by latanoprost."J. Am. Acad. Dermatol.. 44. 721-723 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ichihara T, et al.: "Resistance to fluminant hepatitis and carcinogenesis conferred by overexpression of retinoblastoma protein inmouse liver."HepatoIogy. 33. 948-955 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Reconstitution of hepatic tissue using hepatic stem cells."IGAKU NO AYUMI. 196. 383-386 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Construction of mini-liver using hepatic stem cells."GI Research. 93. 70-77 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Construction of mini-liver using hepatic stem cells."Molecular Medicine. 38. 16-22 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, at al.: "Hepatic stem cell and its differentiation."Acta Hepatologica Japonica. 42. 389-397 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "Role of.ATP7B in biliary copper excretion in a human hepatoma cell line and normal rat hepatocytes."Gastroenterology. 118. 921-928 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Komatsu M, et al.: "Copper transporting P-type adenosine triphosphatase (ATP7B)is associated with Cisplatin resistance."Cancer Res.. 60. 1312-1316 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujfta K, et al.: "Quantitative detection of apoptotic thymocytes in low-dose X-irradiated mice by an anti-single-stranded DNA antibody."J, Radiat Res.. 41. 139-149 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada M, et al.: "Copper does not alter the intracellular distribution of ATP7B, a copper-transporting ATPase"Biochem. Biophys. Res. Commun. 275. 871-876 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yang X. L., et al.: "MFH- 1 is required for bone morphogenetic protein-2-induced osteoblastic differentiation of C2C12 myoblasts"FEBS Letters. 470. 29-34 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Narisawa T, et al.: "Inhibitory effects of ursodeoxycholic acid on N-methyl-nitrosourea-induced colon carcinogenesis and colonic mucosal telomerase activity in F344 rats"J. Exp. Clin. Cancer Res.. 18. 259-266 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Biliary expression of copper in LEG rat after introduction of copper transporting P-type ATPase. ATP7B"FEBS Lett.. 448. 53-56 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "The Long-Evans Cinnamon rat: An animal model for Wilson's disease"Pediatr. Int. 41. 414-418 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sugiyama T, et al.: "Reconstitution ofhepatic tissue using liver stem cells"In Growth, Proliferation, and Apoptosis in Hepatocytes (Okita K., ed.), pp. 100 Springer-Verlag, Tokyo. (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Construction of mini-liver by tissue engineering techniques"In Advanced Medicine for Digestive Diseases (Morioka Y., et al., eds.),pp. 663 Institute of Advanced Medical Techniques, Tokyo. (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Terada K, et al.: "Hepatic stem cell and hair stem cell"In KAGAKU Frontier 3, Regenerative Medical Technology (Ikada Y., ed.) pp. 254, KAGAKU DOJlN, Kyoto. (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 寺田邦彦, 他: "肝幹細胞"Annual Review 消化器 2002. 34-39 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kanzaki A, et al.: "Copper-transporting P-Type Adenosine Triphosphatase (ATP7B) Is Expressed in Human Breast Carcinoma"Jpn. J. Cancer Res.. 93・1. 70-77 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kameda T, et al.: "Acceleration of the formation of cultured epithelium using the sonic hedgehog expressing feeder cells"Tissue Eng.. 7・5. 545-555 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada M, et al.: "A Mutation of Wilson's Disease Protein, ATP7B, Is Degraded in the Proteasomes and Forms Protein Aggregates"Gastroenterology. 120・4. 967-975 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Demitsu T, et al.: "Hypertrichosis induced by latanoprost"J. Am. Acad. Dermatol. 44・4. 721-723 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ichihara T, et al.: "Resistance to fluminant hepatitis and carcinogenesis conferred by overexpression of retinoblastoma protein in mouse liver"Hepatology. 33・4. 948-955 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 寺田邦彦, 他: "肝臓幹細胞とその分化"肝臓. 42・8. 389-397 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 寺田邦彦, 他: "肝幹細胞を利用した肝組織の再構成"医学のあゆみ. 196・5. 383-386 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 寺田邦彦, 他: "幹細胞を用いたミニ肝臓の形成"G.I.Research. 9・3. 51-55 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 寺田邦彦, 他: "幹細胞を用いたミニ肝臓の形成"Molecular Mediceine. 38・1. 16-22 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sugiyama T, et al.: "Reconstitution of hepatic tissue using liver stem cells. (Growth, proliferation, and apoptosis in hepatocytes (Okita K., ed.)"Springer-Verlag, Tokyo. 100 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada M.: "Role of ATP7B in Biliary Copper Excretion in a Human Hepatoma Cell Line and Normal Rat Hepatocytes."Gastroenterology. 118. 921-928 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yang X.L.: "MFH-1 is required for bone morphogenetic protein-2-induced osteoblastic differentiation of C2C12 myoblasts."FEBS Letters. 470. 29-34 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Komatsu M.: "Copper transporting P-type adenosine triphosphatase (ATP7B) is associated with Cisplatin resistance."Cancer Res.. 60. 1312-1316 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagai H: "Genomic DNA analyses of spontaneous hepatocellular carcinomas in LEC rat liver using a new technique."Oncology Report. 7. 315-318 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 寺田邦彦: "幹細胞を用いたミニ肝臓の形成"Molecular Medicine.. 38. 16-20 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 寺田邦彦: "肝幹細胞を利用した肝組織の再構成"医学のあゆみ. 196. 383-386 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 寺田邦彦: "『再生医療工学』"化学同人(印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugiyama T.: "Experimental protocols for reactive oxygen and nitrogen species"Oxford University Press, New York. 400 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nagai H.et al.: "Genomic DNA analyses of spontaneous hepatocellular carcinomas in LEC rat liver using a new technique"Oncology Report. 7. 315-318 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Komatsu M.et al.: "Cisplatin resistance conferred by copper transporting P-type ATPase cDNA (ATP7B)"Cancer Res.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Harada M.et al.: "Wilson's disease gene product,ATP7B localizes in the late endosomes in a human hepatoma cell line and normal rat hepatocytes : Participation in biliary copper"Gastroenterology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Terada K.et al.: "Biliary expression of copper in LEC rat after introduction of copper transporting P-type ATPase,ATP7B"FEBS Lett.. 448. 53-56 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Terada K.et al.: "The Long-Evans Cinnamon rat : An animal model for Wilson's disease"Pediatr.Int.. 41. 414-418 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe I.et al.: "Detection of apoptotic cells in human colorectal cancer by in situ methods : Antibody against single-stranded DNA and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) methods"Jpn.J.Cancer Res.. 90. 188-193 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sugiyama,T. et al.: "Liver stem-like (oval) cells : isolation,differentiation and application for cell therapy,In Ikada,Y.and Okano,T.ed.Tissue Engineering for Therapeutic Use"Elsevier Science B.V.. 161 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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