| Project/Area Number |
10470211
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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 | Kumamoto University |
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Principal Investigator |
TAKAKURA Nobuyuki Molecular Embryology and Genetics Cell Differentiation, Kumamoto University, Associate Professor, 発生医学研究センター, 助教授 (80291954)
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| Co-Investigator(Kenkyū-buntansha) |
SUDA Toshio Molecular Embryology and Genetics Cell Differentiation, Kumamoto University, Professor, 発生医学研究センター, 教授 (60118453)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1998: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Keywords | hematopoietic stem cell / development / endothelial cell / TIE2 / c-Kit / Angiopoietin-1 / P-Sp / アンジオエポエチン / Flk-1 / AGM |
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| Research Abstract |
In the vitelline artery of E9.5 murine embryo, TIE2^+c-Kit^+ hematopoieic stem cells (HSCs) aggregated and adhered to TIE2^+ endothelial cells (ECs). Upon the stimulation of Angiopoietin-1 (Ang1), TIE2^+ HSCs adhered to extra-cellular matrix, such as fibronectin or collagen, mediated by integrin. TIE2 phosphorylation and activation of integrin synergistically promoted inhibition of cell apoptosis, moreover, TIE2 phosphorylation alone could inhibit the cell to drive. Immature hematopoietic progenitor cells (Lin^-c-Kit^+) in the bone marrow can be fractionated into TIE2^+ or TIE2^- cells and TIE2^+ cells have been clarified as the most immature HSCs compared with TIE2^- cells. Interestingly, TIE2^+ HSCs produce Ang1 and Ang1 stimulates TIE2 on HSCs by the autocrine loop. As previously reported, in embryos, the tyrosine kinase receptor (TIE2)-null state is lethal at around E10.5 day after gestation and resulted in defective angiogenesis and hematopoiesis. TIE2^+ HSCs did not locate at vitelline artery TIE2 null embryo. Taken together, TIE2 is essential for adhesion of HSCs to ECs as a stromal cell component and promotion of proliferation affected by the factors produced from ECs. Moreover, we found that Ang1 from HSCs promote angiogenesis. This function suggests that HSCs construct the microenvironment such as fine vascular network in hematopoietic organ and HSCs selectively adhere to ECs for their proliferation or maintenance of immature phenotype in the vascular niche.
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