Self-Renewal of Multipotent Long-Term Repopulating Hematopoietic Stem Cells Is Negatively Regulated by Fas and Tumor Necrosis Factor Receptor Activation

doi:10.1084/jem.194.7.941

Published online 1 October 2001. doi:10.1084/jem.194.7.941

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© The Rockefeller University Press, 0022-1007/2001/10/941/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 7, October 1, 2001 941-952

Original Article

Self-Renewal of Multipotent Long-Term Repopulating Hematopoietic Stem Cells Is Negatively Regulated by Fas and Tumor Necrosis Factor Receptor Activation

David Bryder^a, Veslemøy Ramsfjell^a, Ingunn Dybedal^a, Kim Theilgaard-Mönch^b, Carl-Magnus Högerkorp^a, Jörgen Adolfsson^a, Ole Johan Borge^a, and Sten Eirik W. Jacobsen^a
^a Department of Stem Cell Biology, Institute of Laboratory Medicine, University Hospital of Lund, 221 84 Lund, Sweden
^b The Granulocyte Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark

Correspondence to: Sten Eirik W. Jacobsen, Department of Stem Cell Biology, Institute of Laboratory Medicine, Klinikgatan 26, BMC B12, 221 84 Lund, Sweden. Tel:46-46-222-30-80 Fax:46-46-222-36-00 E-mail:sten.jacobsen{at}stemcell.lu.se.

Multipotent self-renewing hematopoietic stem cells (HSCs) areresponsible for reconstitution of all blood cell lineages. Whereasgrowth stimulatory cytokines have been demonstrated to promoteHSC self-renewal, the potential role of negative regulatorsremains elusive. Receptors for tumor necrosis factor (TNF) andFas ligand have been implicated as regulators of steady-statehematopoiesis, and if overexpressed mediate bone marrow failure.However, it has been proposed that hematopoietic progenitorsrather than stem cells might be targeted by Fas activation.Here, murine Lin^-Sca1⁺c-kit⁺ stem cells revealed little or noconstitutive expression of Fas and failed to respond to an agonisticanti-Fas antibody. However, if induced to undergo self-renewalin the presence of TNF- ${alpha}$ , the entire short and long-term repopulatingHSC pool acquired Fas expression at high levels and concomitantactivation 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 severelyand irreversibly compromised in their short- and long-term multilineagereconstituting ability if activated by TNF- ${alpha}$ or through Fas,providing the first evidence for negative regulators of HSCself-renewal.

Key Words: hematopoietic stem cells, bone marrow transplantation, tumornecrosis factor, Fas, Fas ligand

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