Notch signaling induces apoptosis in primary human CD34+ hematopoietic progenitor cells
Notch signaling induces apoptosis in primary human CD34+ hematopoietic progenitor cells
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DOI：
10.1634/stemcells.2005-0303
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Buckle, Anne-Marie
中科院分区：
文献类型：
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作者：
Chadwick, Nicholas;Nostro, Maria Cristina;Buckle, Anne-Marie
Notch信号调节发育过程中的多种细胞命运决定，并据报道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自我更新的功能后果。用组成型活性人Notch 1胞内结构域（N1 ICD）逆转录病毒转导人脐带血CD 34（+）细胞亚群。N1 ICD转导的细胞在体外增殖程度低于单独用载体转导的细胞，并且这伴随着CD 34（+）细胞群的百分比和绝对数量的减少，包括CD 34（+）Thy（+）Lin（-）HSC。异位N1 ICD表达抑制细胞周期动力学，同时上调p21 mRNA的表达和诱导凋亡。用HES-1（Notch信号传导的已知转录靶点和Notch功能的介体）转导细胞对HSC增殖没有影响，表明Notch诱导效应的机制是HES-1非依赖性的。这项研究的结果表明，Notch信号通路的激活对人造血CD 34（+）细胞群的增殖和存活具有抑制作用。这些发现对促进人类HSC自我更新的策略具有重要意义。
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.