CD34- Cells at the Apex of the Human Hematopoietic Stem Cell Hierarchy Have Distinctive Cellular and Molecular Signatures
CD34- Cells at the Apex of the Human Hematopoietic Stem Cell Hierarchy Have Distinctive Cellular and Molecular Signatures
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DOI：
10.1016/j.stem.2013.05.025
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发表时间：
2013-08-01
期刊：
影响因子：
23.9
通讯作者：
Bonnet, Dominique
中科院分区：
文献类型：
--
作者：
Anjos-Afonso, Fernando;Currie, Erin;Bonnet, Dominique
除了具有良好特性的CD34(+)造血干细胞和祖细胞(HSPC)外，人类造血干细胞(HSC)层次结构还包含罕见的CD34(-)群体，具有严重的联合免疫缺陷-再繁殖能力。然而，对这些CD34(-)细胞的分子特征或它们与CD34(+)群体的关系知之甚少。在这里，我们证明了自我更新的LIN(-)CD34(-)CD38(-)CD93(Hi)群体包含的细胞不仅具有造血干细胞的功能，而且在造血系统中也可以被置于CD34(+)群体之上。这些细胞有一个活跃的Notch通路，其中通过Delta4的信号对维持原始状态至关重要，Jagged1和转化生长因子-β的联合信号对控制其静止非常重要。它们对增殖信号也是不敏感的，表现出部分受Notch调控的典型的Wnt通路。因此，总体而言，CD34(-)细胞代表了一个不成熟和静止的人类HSC群体，通过一个独特的细胞信号相互作用网络维持。
In addition to well-characterized CD34(+) hematopoietic stem and progenitor cells (HSPCs), the human hematopoietic stem cell (HSC) hierarchy contains a rare CD34(-) population with severe combined immunodeficiency-repopulating capacity. However, little is known about the molecular characteristics of these CD34(-) cells or their relationship to the CD34(+) populations. Here, we show that the self-renewing Lin(-)CD34(-)CD38(-)CD93(hi) population contains cells that not only function as HSCs, but can also be placed above the CD34(+) populations in the hematopoietic hierarchy. These cells have an active Notch pathway, in which signaling through Delta4 is crucial for maintenance of the primitive state, and combined signals from Jagged1 and TGF-beta are important in controlling its quiescence. They are also refractory to proliferative signals and show a repressed canonical Wnt pathway, in part regulated by Notch. Overall, therefore, CD34(-) cells represent an immature and quiescent human HSC population maintained through a distinctive network of cellular signaling interactions.