Chadwick Nicholas, Nostro Maria Cristina, Baron Martin, Mottram Rachel, Brady Gerard, Buckle Anne-Marie
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Stem Cells. 2007 Jan;25(1):203-10. doi: 10.1634/stemcells.2005-0303. Epub 2006 Sep 14.
Notch signaling regulates diverse cell fate decisions during development and is reported to promote murine hematopoietic stem cell (HSC) self-renewal. The purpose of this study was to define the functional consequences of activating the Notch signaling pathway on self-renewal in human HSCs. Subsets of human umbilical cord blood CD34(+) cells were retrovirally transduced with the constitutively active human Notch 1 intracellular domain (N1ICD). N1ICD-transduced cells proliferated to a lesser extent in vitro than cells transduced with vector alone, and this was accompanied by a reduction in the percentage and absolute number of CD34(+) cell populations, including CD34(+)Thy(+)Lin(-) HSCs. Ectopic N1ICD expression inhibited cell cycle kinetics concurrent with an upregulation of p21 mRNA expression and induced apoptosis. Transduction of cells with HES-1, a known transcriptional target of Notch signaling and a mediator of Notch function, had no effect on HSC proliferation, indicating that the mechanism of the Notch-induced effect is HES-1-independent. The results of this study show that activation of the Notch signaling pathway has an inhibitory effect on the proliferation and survival of human hematopoietic CD34(+) cells populations. These findings have important implications for strategies aimed at promoting self-renewal of human HSCs.
Notch信号通路在发育过程中调节多种细胞命运决定，据报道可促进小鼠造血干细胞（HSC）的自我更新。本研究的目的是确定激活Notch信号通路对人HSC自我更新的功能影响。用组成型活性人Notch 1细胞内结构域（N1ICD）对人脐带血CD34(+)细胞亚群进行逆转录病毒转导。与仅用载体转导的细胞相比，N1ICD转导的细胞在体外增殖程度较低，同时CD34(+)细胞群体（包括CD34(+)Thy(+)Lin(-) HSC）的百分比和绝对数量减少。异位N1ICD表达抑制细胞周期动力学，同时p21 mRNA表达上调并诱导细胞凋亡。用HES-1（Notch信号通路的已知转录靶点和Notch功能的介质）转导细胞对HSC增殖没有影响，表明Notch诱导效应的机制不依赖于HES-1。本研究结果表明，Notch信号通路的激活对人造血CD34(+)细胞群体的增殖和存活具有抑制作用。这些发现对旨在促进人HSC自我更新的策略具有重要意义。
