Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors
Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors
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DOI：
10.4049/jimmunol.176.9.5267
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Zuniga-Pflucker, Juan Carlos
中科院分区：
文献类型：
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作者：
de Pooter, Renee F.;Schmitt, Thomas M.;Zuniga-Pflucker, Juan Carlos
骨髓和胸腺虽然都是造血环境，但诱导非常不同的分化结果。前者支持造血干细胞的自我更新和多种造血谱系，而后者几乎只支持T淋巴细胞生成。这种区别表明，胸腺环境的行为，以限制造血的命运提供给胸腺移民。在这项研究中，我们证明了Notch配体Delta-like-1（DII-1）的加入，否则支持骨髓生成的体外系统，大大降低了骨髓造血干细胞或未定型祖细胞的潜力。相反，无论DII-1的存在与否，定向髓样祖细胞都成熟。骨髓生成中的阻断是造血祖细胞内Notch信号传导的直接结果，并且DII-1诱导的信号引起锌指转录因子加塔-2表达的快速增加。重要的是，在不存在加塔-2的情况下，DII-1诱导的信号不能抑制向髓样命运的定型。综上所述，我们的结果支持加塔-2在允许DII-1限制非T细胞谱系分化结果中的作用。
The bone marrow and thymus, although both hemopoietic environments, induce very distinct differentiation outcomes. The former supports hemopoietic stem cell self-renewal and multiple hemopoietic lineages, while the latter supports T lymphopoiesis almost exclusively. This distinction suggests that the thymic environment acts to restrict the hemopoietic fates available to thymic immigrants. In this study, we demonstrate that the addition of the Notch ligand Delta-like-1 (DII-1) to an in vitro system that otherwise supports myelopoiesis, greatly reduces the myelopoietic potential of stem cells or uncommitted progenitors. In contrast, committed myeloid progenitors mature regardless of the presence of DII-1. The block in myelopoiesis is the direct result of Notch signaling within the hemopoietic progenitor, and DII-1-induced signals cause a rapid increase in the expression of the zinc finger transcription factor GATA-2. Importantly, in the absence of GATA-2, DII-1-induced signals fail to inhibit commitment to the myeloid fate. Taken together, our results support a role for GATA-2 in allowing DII-1 to restrict non-T cell lineage differentiation outcomes.