| Project/Area Number |
14370297
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | THE UNIVERSITY OF TOKYO |
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Principal Investigator |
IWAMA Atsushi THE UNIVERSITY OF TOKYO, INSTITUTE LECTURER OF MEDICAL SCIENCE, ASSOCIATE PROFESSOR, 医科学研究所, 講師 (70244126)
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| Co-Investigator(Kenkyū-buntansha) |
KOMATSU Norio JICHI MEDICAL SCHOOL, ASSOCIATE PROFESSOR, 血液内科, 助教授 (50186798)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| 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)
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| Keywords | STAT5 / hematopoietic stem cell / self-renewal / thrombopoietin / STAT3 / 自己複製 / STAT |
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| 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.
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