Notch Signaling Induces Apoptosis in Primary Human CD34 super(+) Hematopoietic Progenitor Cells

• Published in: Stem cells (Dayton, Ohio) Ohio), 2007-01, Vol.25 (1), p.203-210
• Main Authors: Chadwick, Nicholas, Nostro, Maria Cristina, Baron, Martin, Mottram, Rachel, Brady, Gerard, Buckle, Anne-Marie
• Format: Article
• Language: English
• ISSN: 1066-5099

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 super(+) 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 super(+) cell populations, including CD34 super(+)Thy super(+)Lin super(-) 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 super(+) cells populations. These findings have important implications for strategies aimed at promoting self-renewal of human HSCs.