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

• Published in: Stem cells (Dayton, Ohio) Vol. 25; no. 1; pp. 203 - 210
• Main Authors: Chadwick, Nicholas, Nostro, Maria Cristina, Baron, Martin, Mottram, Rachel, Brady, Gerard, Buckle, Anne‐Marie
• Format: Journal Article
• Language: English
• Published: Bristol John Wiley & Sons, Ltd 01.01.2007
• Subjects: Antigens, CD34 - immunology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Separation; Coculture Techniques; DNA, Complementary - genetics; Genes, Reporter; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Humans; Luciferases - genetics; Notch; Polymerase Chain Reaction; Receptors, Notch - physiology; Retroviridae - genetics; Stem cell; Stromal Cells - cytology; Stromal Cells - physiology; Transduction, Genetic
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1634/stemcells.2005-0303

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.