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First published online September 14, 2006
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2005-0303v1
25/1/203    most recent
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Submitted on July 6, 2005
Accepted on September 8, 2006

The Stem Cell Niche

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

Nicholas Chadwick 1, Maria C. Nostro 2, Martin Baron 1, Rachel Mottram 1, Gerard Brady 2, Anne-Marie Buckle 1*

1 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
2 Epistem Ltd, Manchester, United Kingdom

* To whom correspondence should be addressed. E-mail: a.buckle{at}umist.ac.uk.


  Abstract

Notch signalling 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 signalling pathway on self-renewal in human HSCs.

Subsets of human umbilical cord blood CD34+ cells were retrovirally transduced with the consitutively 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 signalling 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 signalling 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.

 Key Words. Notch, Hematopoietis, Stem Cell




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