Journal Article

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

Kestler, Hans Armin, Schiemann, Matthias, Zheng, Yi, Scharffetter-Kochanek, Karin, Oostendorp, Robert A. J., Eckl, Christina, Nattamai, Kalpana J., Vas, Virag, Andrä, Immanuel, Dörr, Karin, Marka, Gina, Überle, Bettina, Geiger, Hartmut, Florian, Maria Carolina

2013

Overview

This study identifies a shift from canonical to non-canonical Wnt signalling in ageing haematopoietic stem cells (HSCs); elevated expression of Wnt5a in aged HSCs has a causal role in stem-cell ageing, and this is mediated by the small Rho GTPase Cdc42. Alternate Wnt signals in ageing stem cells The ageing of stem cells is thought to disrupt tissue homeostasis in organs heavily dependent on stem-cell activity, such as the intestine, skin and blood. The underlying mechanistic cause of ageing of stem cells is still not well defined. Here Hartmut Geiger and colleagues identify an unexpected shift from the canonical Wnt signalling pathway — the form commonly observed — to a non-canonical variant in ageing haematopoietic stem cells in mice. They conclude that elevated expression of Wnt5a has a causal role in stem-cell ageing, mediated by the small Rho GTPase Cdc42. Genetic targeting of Wnt5a both attenuates stem-cell ageing and induces functional rejuvenation. 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 , 4 , 5 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/532/7 / 631/532/1542 / 631/532/7 / Aging / Animals / Antibodies / Bone marrow / cdc42 GTP-Binding Protein - metabolism / Cell Differentiation / Cell Polarity / Cellular Senescence / Cellular signal transduction / Female / Haploinsufficiency / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Humanities and Social Sciences / Hypotheses / letter / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Phenotype / Physiological aspects / Proteins / Rejuvenation / Science / Stem cells / Transplantation / Viral antibodies / Wnt Proteins - deficiency / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt Signaling Pathway / Wnt-5a Protein