Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation

Research output: Contribution to journalArticle

Abstract

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-alpha, 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-alpha or through Fas, providing the first evidence for negative regulators of HSC self-renewal.

Details

Authors
  • David Bryder
  • Veslemøy Ramsfjell
  • Ingunn Dybedal
  • Kim Theilgaard-Monch
  • Carl-Magnus Högerkorp
  • Jörgen Adolfsson
  • Ole Johan Borge
  • Sten Eirik W Jacobsen
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • hematopoietic stem cells, bone marrow transplantation, tumor necrosis factor, Fas, Fas ligand
Original languageEnglish
Pages (from-to)941-952
JournalJournal of Experimental Medicine
Volume194
Issue number7
Publication statusPublished - 2001
Publication categoryResearch
Peer-reviewedYes