Hematopoietic stem cell quiescence maintained by p21cip1/waf1
Hematopoietic stem cell quiescence maintained by p21cip1/waf1
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DOI：
10.1126/science.287.5459.1804
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发表时间：
2000-03-10
期刊：
影响因子：
56.9
通讯作者：
Scadden, DT
中科院分区：
文献类型：
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作者：
Cheng, T;Rodrigues, N;Scadden, DT
相对静止是造血干细胞的定义特征，而它们的后代具有显著的增殖能力并不可避免地向终末分化。干细胞的静止已被证实在保护干细胞区室方面具有关键的生物学重要性，我们使用经工程改造而缺乏G（1）检查点调节剂、细胞周期蛋白依赖性激酶抑制剂p21（cip 1/waf 1）（p21）的小鼠直接评估了这一点。在p21的情况下，造血干细胞增殖和绝对数量增加，在正常的稳态条件下。将动物暴露于细胞周期特异性骨髓毒性损伤导致由于造血细胞耗竭而过早死亡。此外，在连续移植的p21（-/-）小鼠骨髓中，原始细胞的自我更新受损，导致造血功能衰竭。因此，p21是控制干细胞进入细胞周期的分子开关，在其缺失的情况下，增加的细胞周期导致干细胞耗竭。在应激条件下，限制细胞循环对于防止干细胞过早耗竭和造血死亡至关重要。
Relative quiescence is a defining characteristic of hematopoietic stem cells, while their progeny have dramatic proliferative ability and inexorably move toward terminal differentiation. The quiescence of stem cells has been conjectured to be of critical biologic importance in protecting the stem cell compartment, which we directly assessed using mice engineered to be deficient in the G(1) checkpoint regulator, cyclin-dependent kinase inhibitor, p21(cip1/waf1) (p21). In the absence of p21, hematopoietic stem cell proliferation and absolute number were increased under normal homeostatic conditions. Exposing the animals to cell cycle-specific myelotoxic injury resulted in premature death due to hematopoietic cell depletion. Further, self-renewal of primitive cells was impaired in serially transplanted bone marrow from p21(-/-) mice, leading to hematopoietic failure. Therefore, p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death.