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Therapeutic strategy for intractable inflammatory bowel diseases by mesenchymal stem cells

Research Project

Project/Area Number 15590675
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionOsaka City University

Principal Investigator

ARAKAWA Tetsuo  Osaka City university, Graduate School of Medicine, Department of Gastroenterology, professor, 大学院・医学研究科, 教授 (60145779)

Co-Investigator(Kenkyū-buntansha) TOMINAGA Kazunari  Osaka City university, Graduate School of Medicine, Department of Gastroenterology, Assistant professor, 大学院・医学研究科, 講師 (80336768)
HIGUCHI Kazuhide  Osaka City university, Graduate School of Medicine, Department of Gastroenterology, Associate professor, 大学院・医学研究科, 助教授 (20218697)
FUJIWARA Yasuhiro  Osaka City university, Graduate School of Medicine, Department of Gastroenterology, Assistant professor, 大学院・医学研究科, 講師 (40285292)
WATANABE Toshio  Osaka City university, Graduate School of Medicine, Department of Gastroenterology, Assistant professor, 大学院・医学研究科, 講師 (50336773)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsInflammatory bowel disease / Mesenchymal stem cell / Differentiation / Regeneration therapy / Inflammation / Wound healing / MAP kinase系 / Apoptosis signal-regulating kinase / 遺伝子治療 / 大腸癌 / 細胞内情報伝達 / 大腸癌細胞 / 胃癌細胞 / 抗癌剤
Research Abstract

Bone marrow-derived cells including a small amount of mesenchymal stem cells (MSCs) had therapeutic effects for clinical human and experimental animal colitis. Its detailed mechanism(s) may be partly mediated by mucosal regeneration, since MSCs have potential for differentiation to several parts of cells. But MSCs was thought to have other functions such as anti-inflammation as well as mucosal regeneration, because anti-inflammatory system is involved in the repair of colitis. We examined the therapeutic efficacy and anti-inflammatory effects of bone marrow-derived MSCs for dextran sulfate sodium (DSS)-induced acute colitis in rats. Experimental colitis was induced by orally administration of 0, 1, 2, or 4% DSS in drinking water for 7 days in inbred male Lewis rats. Bone marrow was extruded from tibias and femurs. Then, its mononuclear cells were isolated and cultured in low-glucose DMEM containing 10% fetal bovine serum for MSCs outgrowth. On 0, 2, and 4 days after the administration … More of DSS, MSCs (5 X 10^6 cells) were injected via tail vein. We checked the volumes of food and water intake, stool condition, and body weight everyday. On day 7, total colon was excised and each colonic mRNA expression of inflammatory cytokines such as TNF-α, IL-1β, IL-10, and COX2 was measured by real time RT-PCR method. We confirmed the MSC's characterization by both the immunostaining for vimentin and α-smooth muscle actin and the cell surface markers such as CD90, the bone marrow progenitor cell marker, but not CD45, HLA-DR, CD11b, nor CD31 using flow cytometric technique. Optimal dose of DSS for the rats used was confirmed at 4% by the assessing for loss of body weight and appetite, bloody fluid stool, and the shortening of colon length. MSC treatment improved the bloody stool and body weight loss, and significantly inhibited the shortening of colon length. At the rectum of MSC-treated rats, expressions of local inflammatory cytokines such as TNF-α and IL-1β were markedly decreased to about 40 and 15%. Local COX2 expression was also suppressed to 15%. IL-10, an anti-inflammatory cytokine, expression was also, decreased to 25%. At the distal colon cite (slightly oral side of rectum), similar tendency was observed about the expressions of cytokines in the MSC-treated colons. These findings suggested that MSC could have the therapeutic efficacy for the experimental colitis via anti-inflammatory functions. Less

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (24 results)

All 2006 2004 Other

All Journal Article (18 results) Publications (6 results)

  • [Journal Article] Anti-inflammatory function induced by bone marrow-derived mesenchymal stem cells for dextran sulfate sodium-induced colitis in rats.2006

    • Author(s)
      Tanaka F, Arakawa T et al.
    • Journal Title

      Ulcer Res 33, Vol2(in press)

    • NAID

      10018262341

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury.2006

    • Author(s)
      Fujiwara Y, Arakawa T et al.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol 290(4)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis.2006

    • Author(s)
      Hayakawa T, Arakawa T et al.
    • Journal Title

      Gut 55(4)

      Pages: 450-456

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Anti-inflammatory function induced by bone marrow-derived mesenchymal stem cells for dextran sulfate sodium-induced colitis in rats.2006

    • Author(s)
      Tanaka F, Tominaga K, Ochi M, Tanigawa T, Sasaki E, Watanabe T, Fujiwara Y, Oshitani N, Higuchi K, Arakawa T
    • Journal Title

      Ulcer Res (in press)

      Pages: 33-33

    • NAID

      10018262341

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury.2006

    • Author(s)
      Fujiwara Y, Higuchi K, Takashima T, Hamaguchi M, Hayakawa T, Tominaga K, Watanabe T, Oshitani N, Shimada Y, Arakawa T
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol. 290(4)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis.2006

    • Author(s)
      Hayakawa T, Fujiwara Y, Hamaguchi M, Sugawa T, Okuyama M, Sasaki E, Watanabe T, Tominaga K, Oshitani N, Higuchi K, Arakawa T
    • Journal Title

      Gut. 55(4)

      Pages: 450-456

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Correlation of MAP kinases with COX-2 induction differs between MKN45 and HT29 cells.2004

    • Author(s)
      Tominaga K, Arakawa T et al.
    • Journal Title

      Aliment Pharmacol Ther 20, Suppl 1

      Pages: 143-150

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Monocytechemotacticprotein-1 regulates leukocyte recruitmentduring gastric ulcer recurrence induced by tumor necrosis factor-alpha.2004

    • Author(s)
      Watanabe T, Arakawa T et al.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol 287(4)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer.2004

    • Author(s)
      Suto R, Arakawa T et al.
    • Journal Title

      Gene Ther 11(2)

      Pages: 187-193

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Correlation of MAP kinases with COX-2 induction differs between MKN45 and HT29 cells.2004

    • Author(s)
      Tominaga K, Higuchi K, Sasaki E, Suto R, Watanabe T, Fujiwara Y, Oshitani N, Matsumoto T, Kim S, Iwao H, Arakawa T
    • Journal Title

      Aliment Pharmacol Ther. 20 Suppl 1

      Pages: 143-150

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Monocyte chemotactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-alpha.2004

    • Author(s)
      Watanabe T, Higuchi K, Hamaguchi M, Shiba M, Tominaga K, Fujiwara Y, Matsumoto T, Arakawa T
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol. 287(4)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dominant-negative mutant of c-Jun gene transfer : a novel therapeutic strategy for colorectal cancer.2004

    • Author(s)
      Suto R, Tominaga K, Mizuguchi H, Sasaki E, Higuchi K, Kim S, Iwao H, Arakawa T
    • Journal Title

      Gene Ther. 11(2)

      Pages: 187-193

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chromic reflux esophagitis.2004

    • Author(s)
      Fujiwara Y et al.
    • Journal Title

      J Gastroenterol Hepatol. 19(5)

      Pages: 521-527

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Has Helicobacter pylori eradication for peptic ulcer been overrated?2004

    • Author(s)
      Arakawa T et al.
    • Journal Title

      Intern Med 43(3)

      Pages: 179-183

    • NAID

      10012708725

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Monocyte chemotactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-alpha.2004

    • Author(s)
      Watanabe T et al.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol 287(4)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prevalence of symptomatic gastro-oesophageal reflux disease in Japanese patients with peptic ulcer disease after eradication of Helicobacter pylori infection.2004

    • Author(s)
      Yamamori K et al.
    • Journal Title

      Aliment Pharmacol Ther 20

      Pages: 107-111

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Correlation of MAP kinases with COX-2 induction differs between MKN45 and HT29 cells.2004

    • Author(s)
      Tominaga K et al.
    • Journal Title

      Aliment Pharmacol Ther 20

      Pages: 43-50

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach.2004

    • Author(s)
      Higuchi K et al.
    • Journal Title

      Drugs Exp Clin Res. 30(5-6)

      Pages: 235-241

    • Related Report
      2004 Annual Research Report
  • [Publications] Montani A et al.: "Food/nutrient intake and risk of atrophicgastritis among the Helicobacter pylori-infected population of northeastern Japan"Cancer Sci. 94. 372-377 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Higuchi K et al.: "Comparison of the effects of rebamipide with those of cimetidine on chronic gatritis associated with Helicobacter pylori in Mongolian gerbils"Aliment Pharmacol Ther. 18. 1-7 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Watanabe Y et al.: "Cigarette smoking and alcohol consumption associated with gastro-oesophageal reflux disease in Japanese men"Scand J Gastroenterol. 38. 807-811 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki E et al.: "COX-2 is essential for EGF induction of cell proliferation in gastric RGM1 cells"Dig Dis Sci. 48. 2257-2262 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanigawa T et al.: "Anti-inflammatory effect of two isoforms of COX in H.pylori-induced gastritis in mice : possible involvement of PGE2"Am J Physiol Gastrointest Liver Physiol. 286. G148-G156 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suto R et al.: "Dominant-negative mutant of c-Jun gene transfer : a novel therapeutic strategy for colorectal cancer"Gene Ther. 11. 187-193 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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