Notch signaling induces apoptosis in primary human CD34+ hematopoietic progenitor cells

Anne-Marie Buckle, Nicholas Chadwick, Maria Cristina Nostro, Martin Baron, Rachel Mottram, Gerard Brady, Anne Marie Buckle

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. ©AlphaMed Press.
    Original languageEnglish
    Pages (from-to)203-210
    Number of pages7
    JournalStem Cells
    Volume25
    Issue number1
    DOIs
    Publication statusPublished - Jan 2007

    Keywords

    • Hematopoiesis
    • Notch
    • Stem cell

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