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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-07-2286.

Submitted July 29, 2002
Accepted February 24, 2003
Human reconstituting hematopoietic stem cells up-regulate Fas expression upon active cell cycling but remain resistant to Fas-induced suppression
Ingunn Dybedal, Liping Yang, David Bryder, Ingbritt Aastrand-Grundstrom, Karin Leandersson, and Sten Eirik W Jacobsen*
Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, University Hospital of Lund, Lund, Sweden
* Corresponding author; email: sten.jacobsen{at}stemcell.lu.se.
The Fas receptor and its ligand have been implicated in mediating the bone marrow (BM) suppression observed in graft versus host disease and a number of other BM failure syndromes. However, previous studies have suggested that Fas is probably not expressed on human hematopoietic stem cells (HSC), but up-regulated as a consequence of their commitment and differentiation, suggesting that progenitors or differentiated blood cells rather than HSC are the targets of Fas-mediated suppression. The present studies confirm that candidate HSC in human cord blood and BM lack constitutive expression of Fas, but demonstrate that Fas expression on CD34+ progenitor and stem cells is correlated to their cell cycle and activation status. Using recently developed in vitro conditions promoting HSC self-renewing divisions, Fas was up-regulated on virtually all HSC capable of multilineage reconstituting NOD-SCID mice in vivo, as well as on long-term culture-initiating cells (LTC-IC). Similarly, in vivo cycling of NOD-SCID repopulating cells upon transplantation, resulted in up-regulation of Fas expression. However, repopulating HSC expressing high levels of Fas remained highly resistant to Fas-mediated suppression, and HSC function was only compromised upon co-activation with tumor necrosis factor. Thus, reconstituting human HSC up-regulate Fas expression upon active cycling, demonstrating that HSC could be targets for Fas-mediated BM suppression.

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