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

Overview

Journal Nature

Specialty Science

Date 2013 Oct 22

PMID 24141946

Citations 164

Authors

Maria Carolina Florian

Kalpana J Nattamai

Karin Dorr

Gina Marka

Bettina Uberle

Virag Vas

Christina Eckl

Immanuel Andra

Matthias Schiemann

Robert A J Oostendorp

Karin Scharffetter-Kochanek

Hans Armin Kestler

Yi Zheng

Hartmut Geiger

Affiliations

Soon will be listed here.

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.

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