Open AccessNotch Signaling Induces Apoptosis in Primary Human CD34 + Hematopoietic Progenitor Cells
Author(s) -
Chadwick Nicholas,
Nostro Maria Cristina,
Baron Martin,
Mottram Rachel,
Brady Gerard,
Buckle AnneMarie
Publication year - 2007
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.2005-0303
Subject(s) - notch signaling pathway , biology , microbiology and biotechnology , haematopoiesis , progenitor cell , stem cell , signal transduction , cd34 , apoptosis , immunology , genetics
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.