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Role of STAT5 in regulation of hematopoietic stem cell function

Research Project

Project/Area Number 14370297
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionTHE UNIVERSITY OF TOKYO

Principal Investigator

IWAMA Atsushi  THE UNIVERSITY OF TOKYO, INSTITUTE LECTURER OF MEDICAL SCIENCE, ASSOCIATE PROFESSOR, 医科学研究所, 講師 (70244126)

Co-Investigator(Kenkyū-buntansha) KOMATSU Norio  JICHI MEDICAL SCHOOL, ASSOCIATE PROFESSOR, 血液内科, 助教授 (50186798)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
KeywordsSTAT5 / hematopoietic stem cell / self-renewal / thrombopoietin / STAT3 / 自己複製 / STAT
Research Abstract

We have previously reported that thrombopoietin (TPO) can support in vitro self-renewal division of murine hematopoietic stem cells (HSCs)(CD34^<-/low> c-Kit^+Sca-1^+ lineage marker-negative, CD34^-KSL). Signal transducers and activators of transcription 5 (STAT5) is one of the major signaling molecules that mediate TPO-elicited signals. In this study, we analyzed the role of STAT5 in HSCs by using constitutively active STAT5 mutant that harbors two amino acid mutations (STAT5 1*6 mutant). Retroviral transduction of STATS 1*6 mutant in purified CD34-KSL HSCs promoted expansion of progenitor cells and multi-lineage differentiation in vitro. After 7 day-culture supplemented with SCF and TPO, the number of high proliferative potential colonies (HPPC) increased ten-fold compared with the GFP control and a half of the HPPC colonies consisted of multi-lineage cells. Notably, even iii the culture supplemented with SCF only, expression of STATS 1*6 in HSCs supported a similar mode of expansion of progenitor cells and multi-lineage differentiation, indicating that activation of STATS can substitute major biological effects of TPO on HSCs. To evaluate the effect of STATS 1*6 in the maintenance of long-term bone marrow repopulating HSC ex vivo, cultured transduced cells corresponding to 20 CD34^-KSL HSCs were transplanted into lethally irradiated mice 7 days after transduction. Long-term bone marrow reconstitution was obtained with STAT5 1*6-expressing cells, but not with GFP control cells, indicating that selective activation of STATS maintains long-term repopulating HSCs ex vivo. Taken together with the impaired bone marrow repopulating ability of STAT5a^<-/-> STAT5b^<-/-> HSCs reported by other groups, our findings support an important role of STAT5 in HSC function. Manipulation of STAT5 activity could be a new approach to maintenance and expansion of HSCs ex vivo.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Miyagi S. et al.: "The Sox-2 regulatory regions display their activities in two distinct multipotent stem cells."Mol.Cell.Biol.. 15. 4207-4220 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Rosenbauer F. et al.: "pDP4, a novel glycoprotein secreted by mature granulocytes is regulated by transcription factor PU.1."Blood. 印刷中. (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki A et al.: "Role for growth factors and extracellular matrix iin controlling differentiation of prospectively isolated hepatic stem cells."Development. 130. 2513-2524 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yotsumoto K. et al.: "Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and -II, regulate mast cell and macrophage myeloid anctivation"J.Exp.Med.. 198. 223-233 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Noguchi E. et al.: "The promoter polymorphism in the eosinophil cationic protein gene and its influence on the serum eosinophil cationic protein level"Am.J.Respir.Crit.Care.Med.. 167. 180-187 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyagi S, Saito T, Mizutani K-I, Masuyama N, Gotoh Y, Iwama A, Makauchi H, Masui S, Niwa H, Nishimoto M, Muramatsu M, Okuda A.: "The Sox-2 regulatory regions display their activities in two distinct multipotent stem cells."Mol.Cell.Biol.. 15. 4207-4220 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Rosenbauer F, Wagner K, Zhang P, Knobeloch K-P, Iwama A, Tenen. DG.: "pDP4, a novel glycoprotein secreted by mature granulocytes is regulated by transcription factor PU.1."Blood[Epub ahead of print]. Feb12(in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Suzuki A, Iwama A, Miyashita H, Nakauchi H, Taniguchi H.: "Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells."Development. 130. 2513-2524 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yotsumoto K, Okoshi Y, Shibuya K, Yamazaki S, Tahara-Hanaoka S, Honda S, Osawa M, Kuroiwa A, Matsuda Y, Tenen DG, Iwama A, Nakauchi H, Shibuya A: "Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and -II, regulate mast cell and macrophage myeloid activation."J.Exp.Med.. 198. 223-233 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Osawa M, Yamaguchi T, Nakamura Y, Kaneko S, Onodera M, Sawada K-I, Nakauchi H, Iwama A.: "Erythroid expansion mediated by Gfi-1B zinc finger protein : its implication in normal hematopoiesis."Blood. 100. 2769-2777 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hirasawa R, Shimizu R, Takahashi S, Osawa M, Takayanagi S, Kato Y, Onodera M, Minegishi N, Yamamoto M, Fu ao K, Taniguchi H, Nakauch, H, Iwama A.: "Essential and instructive roles of GATA factors in eosinophil development."J.Exp.Med.. 195. 1379-1386 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Miyagi S.et al.: "The Sox-2 regulatory regions display their activities in two distinct multipotent stem cells"Mol.Cell.Biol. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Rosenbauer F.et al.: "pDP4, a novel glycoprotein secreted by mature granulocytes is regulated by transcription factor PU.1."Blood. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki A.et al.: "Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells."Development. 130. 2513-2524 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yotsumoto K.et al.: "Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and -II, regulate mast cell and macrophage myeloid activation."J.Exp.Med.. 198. 223-233 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Noguchi E.et al.: "The promoter polymorphism in the eosinophil cationic protein gene and its influence on the serum eosinophil cationic protein level."Am.J.Respir.Crit.Care.Med.. 167. 180-184 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Osawa M et al.: "Erythroid expansion mediated by Gfi-1B zinc finger protein : its implication in normal hematopoiesis"Blood. 100. 2769-2777 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Reddy VA et al.: "The granulocytic inducer C/EBP α inactivates the myeloid master regulator PU.1 : possible role in lineage commitment decisions"Blood. 100. 483-490 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwama A et al.: "Reciprocal roles for C/EBP and PU.1 transcription factors in Langerhans cell commitment"J. Exp. Med.. 195. 547-558 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hirasawa R et al.: "Essential and instructive roles of GATA factors in eosinophil development"J. Exp. Med.. 195. 1379-1386 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Morotomi-Yano K et al.: "Human RFX4 is a testis-specific transcription factor that interacts physically with other human RFX members"J. Biol. Chem.. 277. 836-842 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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