Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor receptor activation.
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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DOI：
10.1084/jem.194.7.941
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发表时间：
2001-10-01
期刊：
影响因子：
--
通讯作者：
Jacobsen SE
中科院分区：
文献类型：
--
作者：
Bryder D;Ramsfjell V;Dybedal I;Theilgaard-Mönch K;Högerkorp CM;Adolfsson J;Borge OJ;Jacobsen SE
多能自我更新造血干细胞（HSC）负责所有血细胞谱系的重建。尽管生长刺激性细胞因子已被证明可促进HSC自我更新，但负调节因子的潜在作用仍然难以捉摸。肿瘤坏死因子（TNF）和Fas配体的受体已被认为是稳态造血的调节因子，如果过度表达，则介导骨髓衰竭。然而，有人提出，造血祖细胞，而不是干细胞可能是Fas激活的目标。在这里，小鼠Lin− Sca 1 +c-kit+干细胞显示Fas的组成性表达很少或没有，并且未能对激动性抗Fas抗体产生应答。然而，如果在TNF-α存在下诱导进行自我更新，则整个短期和长期再增殖的HSC池获得高水平的Fas表达，并且Fas的伴随激活抑制了在单细胞水平培养的Lin− Sca 1 +c-kit+细胞的体外生长。此外，在体外进行自我更新分裂的Lin− Sca 1 +c-kit+干细胞，如果被TNF-α或Fas激活，其短期和长期多谱系重建能力会受到严重和不可逆的损害，这为HSC自我更新的负调节提供了第一个证据。
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-α, 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-α or through Fas, providing the first evidence for negative regulators of HSC self-renewal.
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影响因子：
2.6
作者：
Ito, T;Tajima, F;Ogawa, M
通讯作者：
Ogawa, M
影响因子：
20.3
作者：
Aguila, HL;Weissman, IL
通讯作者：
Weissman, IL
DOI：
10.1073/pnas.91.22.10695
发表时间：
1994-10-25
影响因子：
11.1
作者：
JACOBSEN, FW;ROTHE, M;JACOBSEN, SEW
通讯作者：
JACOBSEN, SEW
影响因子：
20.3
作者：
Bryder, D;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
4.4
作者：
Lee, SJ;Zhou, T;Benveniste, EN
通讯作者：
Benveniste, EN