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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.

Type

Journal article

Journal

J Exp Med

Publication Date

01/10/2001

Volume

194

Pages

941 - 952

Keywords

Animals, Antigens, CD34, Antigens, CD95, Antigens, Ly, Bone Marrow Transplantation, Cell Division, Cell Separation, Cells, Cultured, Hematopoiesis, Hematopoietic Stem Cells, Membrane Proteins, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-kit, Receptors, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha