Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation.
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Journal of Experimental Medicine |
Volume | 194 |
Issue number | 7 |
Pages (from-to) | 941-52 |
Number of pages | 11 |
ISSN | 0022-1007 |
Publication status | Published - 2001 |
Externally published | Yes |
Bibliographical note
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
ID: 5142990