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Cdc42 活性调节造血干细胞衰老和更新。

Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation.

机构信息

Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany.

出版信息

Cell Stem Cell. 2012 May 4;10(5):520-30. doi: 10.1016/j.stem.2012.04.007.

Abstract

The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.

摘要

衰老过程中造血功能的下降涉及免疫反应的逐渐减弱和髓系恶性肿瘤发病率的增加,这与造血干细胞(HSCs)的衰老有关。HSC 衰老的分子机制尚不清楚。在这里,我们证明了衰老 HSCs 中小 RhoGTPase Cdc42 的活性升高与 HSC 衰老有关,并与衰老 HSCs 中极性的丧失相关。Cdc42 活性的药理学抑制可使衰老 HSCs 功能上恢复活力,增加衰老 HSC 群体中极化细胞的百分比,并恢复组蛋白 H4 赖氨酸 16 乙酰化的水平和空间分布,使其状态类似于年轻 HSCs。因此,我们的数据表明 Cdc42 活性在 HSC 生物学和表观遗传调控中具有机制作用,并将 Cdc42 活性确定为改善干细胞衰老的药理学靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c9e/3348626/732781c8cc64/nihms370276f1.jpg

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