Cell Stem Cell：Cdc42活性可调节造血干细胞的衰老和活力

sylar.wy

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5月4日，国际期刊Cell Stem Cell发表了德国乌尔姆大学、美国辛辛那提儿童医院医学中心和辛辛那提大学等处科学家合作研究的发现，Cdc42的活性可调节造血干细胞（HSC，hematopoietic stem cells）的衰老和活力。
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然而此前，科学家普遍认为造血干细胞的衰老由细胞内部某种机制控制，无法通过治疗干预扭转。( ~$ Q& o% h+ U. v3 ?  E

! a; A1 f% w) @4 e1 _1 r在衰老过程中，造血功能随之下降，免疫反应也逐渐减弱，而骨髓瘤的发生率上升。造血干细胞衰老的分子机制尚不清楚。研究人员发现，提高造血干细胞中小RhoGTPase Cdc42的活力可促进造血干细胞的衰老，且衰老的造血干细胞失去极性。
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8 N- G; ^" b$ e$ f若采用药物抑制Cdc42的活性，衰老的造血干细胞活力重新恢复，极性造血干细胞所占总衰老造血干细胞的比例也增加。同时，组蛋白H4的16位赖氨酸乙酰化水平也恢复到年轻造血干细胞的水平。3 ~+ M. M0 s; S0 N

7 C. T0 c* }& l6 a3 zGWAS结果也表明Cdc42在人白细胞中的表达量与发病和衰老呈正相关。衰老小鼠的多种组织中也发现Cdc42的活性增高。
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. H& `( w3 ^1 |6 O: M可见，Cdc42在造血干细胞的表观调节中发挥重要作用，它可作为缓解造血干细胞衰老的药物靶点。

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Cdc42 Activity Regulates Hematopoietic Stem Cell Aging and Rejuvenation- Q% S7 e/ X7 v: t! c' P' w! r

, O5 a1 J" ~* X; D+ Q, VMaria Carolina Florian1, Karin D?rr1, Anja Niebel1, Deidre Daria1, Hubert Schrezenmeier2, Markus Rojewski2, Marie-Dominique Filippi3, Anja Hasenberg4, Matthias Gunzer4, Karin Scharffetter-Kochanek1, Yi Zheng3, Hartmut Geiger
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. I' W2 W: M3 K9 FThe 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.

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