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

Bryder, David LU ; Ramsfjell, Veslemøy; Dybedal, Ingunn; Theilgaard-Monch, Kim; Högerkorp, Carl-Magnus LU ; Adolfsson, Jörgen LU ; Borge, Ole Johan and Jacobsen, Sten Eirik W LU (2001) In Journal of Experimental Medicine 194(7). p.941-952
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hematopoietic stem cells, bone marrow transplantation, tumor necrosis factor, Fas, Fas ligand
in
Journal of Experimental Medicine
volume
194
issue
7
pages
941 - 952
publisher
Rockefeller University Press
external identifiers
  • pmid:11581316
  • scopus:0035477090
ISSN
1540-9538
DOI
10.1084/jem.194.7.941
language
English
LU publication?
yes
id
ae975bcf-dc68-4323-9708-cd5fb06b507f (old id 1121566)
date added to LUP
2008-06-25 14:21:27
date last changed
2018-01-07 09:47:16
@article{ae975bcf-dc68-4323-9708-cd5fb06b507f,
  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.},
  author       = {Bryder, David and Ramsfjell, Veslemøy and Dybedal, Ingunn and Theilgaard-Monch, Kim and Högerkorp, Carl-Magnus and Adolfsson, Jörgen and Borge, Ole Johan and Jacobsen, Sten Eirik W},
  issn         = {1540-9538},
  keyword      = {hematopoietic stem cells,bone marrow transplantation,tumor necrosis factor,Fas,Fas ligand},
  language     = {eng},
  number       = {7},
  pages        = {941--952},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation},
  url          = {http://dx.doi.org/10.1084/jem.194.7.941},
  volume       = {194},
  year         = {2001},
}