| Project/Area Number |
18K16080
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Yamanashi |
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Principal Investigator |
Otake Shimon 山梨大学, 大学院総合研究部, 助教 (50813060)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | CLEC-2 / 赤血球造血 / 骨髄間質細胞 / 巨核球 / 骨髄微小環境 / ポドプラニン / 赤芽球造血 / Podoplanin / 血小板 |
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| Outline of Final Research Achievements |
CLEC-2 is a podoplanin (PDPN) receptor expressed on the surface of platelets and megakaryocytes (Mgk). We have previously reported that PDPN+ bone marrow (BM) stromal cells facilitate Mgk expansion and maturation through the CLEC-2/PDPN axis. Although deletion of Mgk/platelet CLEC-2 causes anemia, its contribution to erythropoiesis remains unknown. To reveal the mechanism of this anemia, we first obtained BM cells from CLEC-2 conditional KO (cKO) mice and analyzed them using flow cytometry. In the CLEC-2 cKO mice, the number of TER119+ erythroblasts was decreased due to increased apoptosis. In vitro experiments showed that PDPN+ bone marrow stromal cells secreted IGF-1 upon stimulation with CLEC-2. In CLEC-2 cKO mice, IGF-1 concentrations in serum and BM extracellular fluid were decreased. These data reveal a novel mechanism of erythropoiesis regulation; BM microenvironment consisting of Mgk and PDPN+ stromal cells supports erythropoiesis via appropriate secretion of IGF-1.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において，巨核球が発現するCLEC-2と，そのリガンドであるポドプラニンが赤芽球造血に影響をすることを特定した．すでに系統の決定した血球細胞が，他の系統の造血に影響を及ぼしているという機序はユニークであり，学術的な興味を惹かれるものである．また，高齢者における貧血症の1/3は原因が不明であるとされる．本研究で特定されたCLEC-2-ポドプラニン軸を介したIGF-1の分泌制御機構の解明は，これまで原因不明であった貧血の機序解明にもつながる可能性がある．
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