Display Settings:

Format

Send to:

Choose Destination
Nature. 2013 Nov 21;503(7476):392-6. doi: 10.1038/nature12631. Epub 2013 Oct 20.

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

Author information

  • 1Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany.

Abstract

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 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. 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.

Comment in

PMID:
24141946
[PubMed - indexed for MEDLINE]
PMCID:
PMC4078992
Free PMC Article

Images from this publication.See all images (10)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Extended Data Figure 1
Extended Data Figure 2
Extended Data Figure 3
Extended Data Figure 4
Extended Data Figure 5
Extended Data Figure 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk