A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing

作者：Florian Maria Carolina; Nattamai Kalpana J; Doerr Karin; Marka Gina; Ueberle Bettina; Vas Virag; Eckl Christina; Andrae Immanuel; Schiemann Matthias; Oostendorp Robert A J; Scharffetter Kochanek Karin; Kestler Hans Armin; Zheng Yi; Geiger Hartmut^*

来源：Nature, 2013, 503(7476): 392-+.

DOI：10.1038/nature12631

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(1,2). Ageing results in the inability of these tissues to 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(3-6). 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-intrinsic non-canonical Wnt5a signalling in HSC ageing.

• 出版日期2013-11-21
• 单位河北医科大学