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Original Article |
sten.jacobsen{at}stemcell.lu.se
Multipotent self-renewing hematopoietic stem cells (HSCs) are responsible for reconstitution of all blood cell lineages. Whereas growth stimulatory cytokines have been demonstrated to promote HSC self-renewal, the potential role of negative regulators remains elusive. Receptors for tumor necrosis factor (TNF) and Fas ligand have been implicated as regulators of steady-state hematopoiesis, and if overexpressed mediate bone marrow failure. However, it has been proposed that hematopoietic progenitors rather than stem cells might be targeted by Fas activation. Here, murine Lin–Sca1+c-kit+ stem cells revealed little or no constitutive expression of Fas and failed to respond to an agonistic anti-Fas antibody. However, if induced to undergo self-renewal in the presence of TNF-
, the entire short and long-term repopulating HSC pool acquired Fas expression at high levels and concomitant activation of Fas suppressed in vitro growth of Lin–Sca1+c-kit+ cells cultured at the single cell level. Moreover, Lin–Sca1+c-kit+ stem cells undergoing self-renewal divisions in vitro were severely and irreversibly compromised in their short- and long-term multilineage reconstituting ability if activated by TNF- or through Fas, providing the first evidence for negative regulators of HSC self-renewal.
Key Words: hematopoietic stem cells • bone marrow transplantation • tumor necrosis factor • Fas • Fas ligand
Abbreviations used in this paper: BM, bone marrow; GVHD, graft versus host disease; HSC, hematopoietic stem cell; LTRC, long-term repopulating cell; PB, peripheral blood.
© 2001 The Rockefeller University Press
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