A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing.
A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing.
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许多具有高细胞更新率的器官（例如皮肤，肠道和血液）由短寿命细胞组成，需要体干细胞的持续补充。衰老导致这些组织无法维持体内平衡，并且据信体干细胞衰老是随着年龄或与年龄相关的疾病的组织磨损的一个潜在原因。造血干细胞（HSC）的老化与老年人造血功能受损有关。尽管有大量的数据描述了衰老过程中HSC功能的下降，但这一过程的分子机制在很大程度上仍然未知，这排除了合理的方法来减缓干细胞衰老。在这里，我们报告了一个意想不到的转变，从经典的非经典的Wnt信号在小鼠由于在老化的HSC，这导致干细胞老化的Wnt5a的表达升高。Wnt5a处理年轻的HSC诱导衰老相关的干细胞非极性，再生能力的降低和衰老样骨髓淋巴样分化通过小Rho GT3 Cdc42的激活偏斜。相反，Wnt5a单倍不足减弱HSC老化，而Wnt5a表达的干细胞内在减少导致功能上再生的老化HSC。我们的数据表明，干细胞内在的非经典Wnt5a信号在HSC衰老中的关键作用。
Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissuesto maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid–lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsicnon-canonical Wnt5a signalling in HSC ageing.
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影响因子：
64.5
作者：
Sugimura R;He XC;Venkatraman A;Arai F;Box A;Semerad C;Haug JS;Peng L;Zhong XB;Suda T;Li L
通讯作者：
Li L
影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut
影响因子：
11.4
作者：
Kühl, M;Sheldahl, LC;Moon, RT
通讯作者：
Moon, RT
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
2.6
作者：
Li, ZX;Schwieger, M;Baum, C
通讯作者：
Baum, C