A Canonical to Non-Canonical Wnt Signalling Switch in Haematopoietic Stem-Cell Ageing

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Polarity
  • Cellular Senescence*
  • Female
  • Haploinsufficiency
  • Hematopoietic Stem Cells / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Rejuvenation
  • Wnt Proteins / deficiency
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • Wnt-5a Protein
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • Cdc42 protein, mouse
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt5a protein, mouse
  • cdc42 GTP-Binding Protein