Hematopoietic stem cell fate is established by the Notch-Runx pathway
Hematopoietic stem cell fate is established by the Notch-Runx pathway
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DOI：
10.1101/gad.1337005
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发表时间：
2005-10-01
影响因子：
10.5
通讯作者：
Zon, LI
中科院分区：
文献类型：
--
作者：
Burns, CE;Traver, D;Zon, LI
鉴定调节造血干细胞（HSC）特化、自我更新和扩增的分子途径仍然是基础和临床生物学的基本目标。在这里，我们分析了Notch信号对斑马鱼发育和成年期HSC数量的影响，定义了干细胞特化的关键途径。Notch信号突变的思维炸弹显示正常的胚胎造血功能，但未能指定成人HSC。令人惊讶的是，通过诱导型转基因系统在胚胎发生过程中的瞬时Notch激活导致了肝星状细胞在性腺-中肾（AGM）区域的Runx 1依赖性扩增。在受辐射的成年人中，Notch活性诱导runx 1基因表达，并使骨髓中的多谱系造血前体细胞增加约三倍。这种增加之后是所有成熟血细胞谱系的加速恢复。这些数据将Notch-Runx途径定义为对HSC命运的发育特化和随后的HSC数量的稳态至关重要，从而提供了用于在体内扩增干细胞的机制。
identifying the molecular pathways regulating hematopoictic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch-Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.