Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2001
Språk
Engelska
Sidor
941-952
Publikation/Tidskrift/Serie
Journal of Experimental Medicine
Volym
194
Issue
7
Dokumenttyp
Artikel i tidskrift
Förlag
Rockefeller University Press
Ämne
- Cell and Molecular Biology
Nyckelord
- hematopoietic stem cells
- bone marrow transplantation
- tumor necrosis factor
- Fas
- Fas ligand
Status
Published
Forskningsgrupp
- Immunology
ISBN/ISSN/Övrigt
- ISSN: 1540-9538