Center for Integrated Medical Research, Keio University School of Medicine, Tokyo, Japan.
PLoS One. 2012;7(11):e51073. doi: 10.1371/journal.pone.0051073. Epub 2012 Nov 30.
A cytokine/stress signaling kinase Tak1 (Map3k7) deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs) harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2) using a competitive transplantation assay in a mouse model. Tak1 single or Tab1/Tab2 double deletions completely eliminated the reconstitution activity of HSCs, whereas Tab1 or Tab2 single deletion did not cause any abnormality. Tak1 single or Tab1/Tab2 double deficient lineage-negative, Sca-1(+), c-Kit(+) (LSK) cells did not proliferate and underwent cell death. We found that Tnfr1 deficiency restored the reconstitution activity of Tak1 deficient bone marrow cells for 6-18 weeks. However, the reconstitution activity of Tak1- and Tnfr1-double deficient bone marrow cells declined over the long term, and the number of phenotypically identified long-term hematopoietic stem cells were diminished. Our results indicate that TAB1- or TAB2-dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms: one is prevention of TNF-dependent cell death and the other is TNF-independent maintenance of long-term HSC.
已知细胞因子/应激信号激酶 Tak1（Map3k7）的缺失会损害造血祖细胞。然而，TAK1 信号在造血系统干细胞功能中的作用尚未得到很好的定义。在这里，我们使用小鼠模型中的竞争移植测定法，对携带 Tak1 及其激活剂、Tak1 结合蛋白 1 和 2（Tab1 和 Tab2）缺失的造血干细胞（HSCs）进行了表征。Tak1 单缺失或 Tab1/Tab2 双缺失完全消除了 HSCs 的重建活性，而 Tab1 或 Tab2 单缺失则不会引起任何异常。Tak1 单缺失或 Tab1/Tab2 双缺失的谱系阴性、Sca-1(+)、c-Kit(+)（LSK）细胞无法增殖并发生细胞死亡。我们发现 Tnfr1 缺失恢复了 Tak1 缺失骨髓细胞在 6-18 周内的重建活性。然而，Tak1 和 Tnfr1 双缺失骨髓细胞的重建活性在长期内下降，并且表型鉴定的长期造血干细胞数量减少。我们的结果表明，TAB1-或 TAB2-依赖性 TAK1 激活是通过两种机制维持造血系统的：一种是防止 TNF 依赖性细胞死亡，另一种是 TNF 非依赖性维持长期 HSC。
