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

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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; Ramsfjell, Veslemøy; Dybedal, Ingunn; Theilgaard-Monch, Kim; Högerkorp, Carl-Magnus; Adolfsson, Jörgen; Borge, Ole Johan; Jacobsen, Sten Eirik W.

In: Journal of Experimental Medicine, Vol. 194, No. 7, 2001, p. 941-952.

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Bryder, David ; Ramsfjell, Veslemøy ; Dybedal, Ingunn ; Theilgaard-Monch, Kim ; Högerkorp, Carl-Magnus ; Adolfsson, Jörgen ; Borge, Ole Johan ; Jacobsen, Sten Eirik W. / Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation. In: Journal of Experimental Medicine. 2001 ; Vol. 194, No. 7. pp. 941-952.

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TY - JOUR

T1 - Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation

AU - Bryder, David

AU - Ramsfjell, Veslemøy

AU - Dybedal, Ingunn

AU - Theilgaard-Monch, Kim

AU - Högerkorp, Carl-Magnus

AU - Adolfsson, Jörgen

AU - Borge, Ole Johan

AU - Jacobsen, Sten Eirik W

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - hematopoietic stem cells

KW - bone marrow transplantation

KW - tumor necrosis factor

KW - Fas

KW - Fas ligand

U2 - 10.1084/jem.194.7.941

DO - 10.1084/jem.194.7.941

M3 - Article

VL - 194

SP - 941

EP - 952

JO - Journal of Experimental Medicine

T2 - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 1540-9538

IS - 7

ER -