CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow.
CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow.
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DOI：
10.1084/jem.20150057
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发表时间：
2015-11-16
期刊：
影响因子：
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通讯作者：
Suda T
中科院分区：
文献类型：
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作者：
Nakamura-Ishizu A;Takubo K;Kobayashi H;Suzuki-Inoue K;Suda T
Nakamura-Ishizu等人。据报道，巨核细胞通过CLEC-2介导的Thpo和其他HSC功能的关键调节因子的产生，发挥着维持HSC静止的利基作用。这些发现可能使HSCs的临床应用成为可能。造血干细胞(HSCs)依赖于骨髓(BM)生态位来维持、增殖和分化。骨髓龛由非造血细胞和成熟造血细胞组成，包括巨核细胞(MKs)。血小板生成素(Thpo)是骨髓细胞分泌的一种重要细胞因子。然而，造血干细胞主要依赖的Thpo的细胞来源尚不清楚。此外，还没有发现调节骨髓中Thpo产生的特定分子途径。在这里，我们证明了膜蛋白C型凝集素样受体-2(CLEC-2)介导了THPO等因子在MKS中的产生。MKS中CLEC2基因条件缺失的小鼠(Clec2MkΔ/Δ)在MKS中产生较低水平的Thpo。CLEC-2缺陷的MKS表现出与CLEC-2相关的信号分子Syk、Lcp2和PLCG2的下调。这些分子在培养的巨噬细胞中被敲除后，Thpo的表达减少。Clec2MkΔ/Δ小鼠表现出骨髓间充质干细胞静止和再生潜能降低，并伴有髓外造血。低水平的Thpo产生可能是Clec2MkΔ/Δ小鼠造血干细胞潜能下降的原因，因为给Clec2MkΔ/Δ小鼠注射重组Thpo可以恢复干细胞潜能。我们的研究确认CLEC-2信号是一种新的分子机制，调节Thpo的产生和其他维持HSCs的因素。
Nakamura-Ishizu et al. report that megakaryocytes function as a niche to maintain HSC quiescence through CLEC-2–mediated production of Thpo and other key regulators of HSC function. These findings could enable manipulation of HSCs for clinical application. Hematopoietic stem cells (HSCs) depend on the bone marrow (BM) niche for their maintenance, proliferation, and differentiation. The BM niche is composed of nonhematopoietic and mature hematopoietic cells, including megakaryocytes (Mks). Thrombopoietin (Thpo) is a crucial cytokine produced by BM niche cells. However, the cellular source of Thpo, upon which HSCs primarily depend, is unclear. Moreover, no specific molecular pathway for the regulation of Thpo production in the BM has been identified. Here, we demonstrate that the membrane protein C-type lectin-like receptor-2 (CLEC-2) mediates the production of Thpo and other factors in Mks. Mice conditionally deleted for CLEC-2 in Mks (Clec2MkΔ/Δ) produced lower levels of Thpo in Mks. CLEC-2–deficient Mks showed down-regulation of CLEC-2–related signaling molecules Syk, Lcp2, and Plcg2. Knockdown of these molecules in cultured Mks decreased expression of Thpo. Clec2MkΔ/Δ mice exhibited reduced BM HSC quiescence and repopulation potential, along with extramedullary hematopoiesis. The low level of Thpo production may account for the decline in HSC potential in Clec2MkΔ/Δ mice, as administration of recombinant Thpo to Clec2MkΔ/Δ mice restored stem cell potential. Our study identifies CLEC-2 signaling as a novel molecular mechanism mediating the production of Thpo and other factors for the maintenance of HSCs.