1] Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China [2] Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena 07745, Germany.
Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou 310036, China.
Nat Commun. 2015 Apr 16;6:6808. doi: 10.1038/ncomms7808.
Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age. Wip1-deficient (Wip1(-/-)) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity. Deletion of p53 rescued the multilineage repopulation defect of Wip1(-/-) HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways. However, p53 deletion did not influence the increased HSC pool size in Wip1(-/-) mice. Interestingly, the expansion of HSCs in Wip1(-/-) mice was due to an mTORC1-mediated HSC proliferation. Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1.
野生型 p53 诱导的磷酸酶 1（Wip1）负调控几种肿瘤抑制因子和 DNA 损伤反应途径。然而，Wip1 对造血干细胞（HSC）稳态和衰老的影响尚不清楚。本文中，作者表明 Wip1 在 HSCs 中高度表达，但随年龄增长而降低。Wip1 缺陷（Wip1(-/-)）小鼠表现出多方面的 HSC 衰老表型，包括增加的细胞库大小和受损的重编程活性。p53 的缺失挽救了 Wip1(-/-) HSCs 的多谱系重编程缺陷，而不影响细胞衰老或凋亡，表明 Wip1-p53 轴以独立于传统 p53 途径的方式调节 HSC 分化。然而，p53 的缺失并不影响 Wip1(-/-) 小鼠中 HSC 库的增加。有趣的是，Wip1(-/-) 小鼠中 HSCs 的扩增是由于 mTORC1 介导的 HSC 增殖。因此，本研究揭示了一种干细胞衰老的机制，其中 p53 和 mTORC1 途径对 HSC 衰老的不同影响受 Wip1 调控。
