Maillard Ivan, Koch Ute, Dumortier Alexis, Shestova Olga, Xu Lanwei, Sai Hong, Pross Seth E, Aster Jon C, Bhandoola Avinash, Radtke Freddy, Pear Warren S
Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Stem Cell. 2008 Apr 10;2(4):356-66. doi: 10.1016/j.stem.2008.02.011.
Gain-of-function experiments have demonstrated the potential of Notch signals to expand primitive hematopoietic progenitors, but whether Notch physiologically regulates hematopoietic stem cell (HSC) homeostasis in vivo is unclear. To answer this question, we evaluated the effect of global deficiencies of canonical Notch signaling in rigorous HSC assays. Hematopoietic progenitors expressing dominant-negative Mastermind-like1 (DNMAML), a potent inhibitor of Notch-mediated transcriptional activation, achieved stable long-term reconstitution of irradiated hosts and showed a normal frequency of progenitor fractions enriched for long-term HSCs. Similar results were observed with cells lacking CSL/RBPJ, a DNA-binding factor that is required for canonical Notch signaling. Notch-deprived progenitors provided normal long-term reconstitution after secondary competitive transplantation. Furthermore, Notch target genes were expressed at low levels in primitive hematopoietic progenitors. Taken together, these results rule out an essential physiological role for cell-autonomous canonical Notch signals in HSC maintenance.
功能获得性实验已证明Notch信号具有扩展原始造血祖细胞的潜力，但Notch是否在体内对造血干细胞（HSC）稳态进行生理调节尚不清楚。为回答这个问题，我们在严格的HSC分析中评估了经典Notch信号整体缺陷的影响。表达显性负性Mastermind样蛋白1（DNMAML，一种Notch介导的转录激活的有效抑制剂）的造血祖细胞实现了对受辐照宿主的稳定长期重建，并显示出富含长期HSC的祖细胞组分频率正常。在缺乏CSL/RBPJ（经典Notch信号所需的一种DNA结合因子）的细胞中也观察到了类似结果。Notch缺失的祖细胞在二次竞争性移植后提供了正常的长期重建。此外，Notch靶基因在原始造血祖细胞中低水平表达。综上所述，这些结果排除了细胞自主经典Notch信号在HSC维持中的重要生理作用。
