演題詳細

一般口演 / Oral Session

一般口演 15 (Oral Session 15) :造血環境

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日程
2013年10月11日(金)
時間
10:00 - 11:30
会場
第13会場 / Room No.13 (札幌市教育文化会館 3F 研修室301)
座長・司会
北島 健二 (Kenji Kitajima):1
1:東京臨床医学総合研究所 幹細胞プロジェクト
 
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Megakaryocytes form a distinctive hematopoietic stem cell niche through expressions of CLEC-2

演題番号 : OS-1-71

石津 綾子 (Ayako Ishizu):1、田久保 圭誉 (Keiyo Takubo):1、須田 年生 (Toshio Suda):1

1:Keio University, Dept of Cell and Differentiation, Tokyo, Japan

 

The bone marrow (BM) niche governs the integrity of hematopoietic stem cells (HSCs). While non-hematopoietic cells mainly constitute the niche, we focused on mature hematopoietic cells, megakaryocytes (Mgk), and their influence on HSCs. Long term (LT-)HSCs reside closely to Mgks in the BM. Genetic and neutralizing antibody oriented ablation specific of Mgks resulted in a drastic loss in LT-HSCs and reduced their repopulation potential. Specific deletion of platelet activation receptor C-type lectin like receptor-2 (CLEC-2) on Mgk lineages (PF4Cre:CLEC-2floxed/floxed; Clec2Pltδ/δ) confined the function of BM HSCs; Clec2Pltδ/δ LT-HSCs showed reduced cell cycle quiescence and lower post-transplantation chimerisms in a competitive BM transplantation assay. Clec2Pltδ/δ mice exhibited abnormal HSC mobilization to the peripheral blood and splenomegaly due to extramedullary hematopoiesis reflecting a failure of Clec2Pltδ/δ BMs to sustain HSCs. Although Clec2Pltδ/δ Mgk progenitors matured without arrest in normal ploidy, sorted Clec2Pltδ/δ Mgks failed to maintain LT-HSC populations in vitro. Cultured Clec2Pltδ/δ Mgks exhibited low mRNA expressions of various niche factors including TPO, TGF-β, KitL and osteopontin. Furthermore, despite presenting thrombocytopenia, serum, BM and spleen TPO levels were remarkably low in Clec2Pltδ/δ mice. Taken together, through CLEC-2 expression, Mgks formulate a niche for the maintenance of HSCs, possibly through niche factor secretion. We identify Mgks as a novel entity to the HSC niche along with an eminent delineation of systemic TPO regulation.

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