A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing
| Autor: | Hartmut Geiger, Gina Marka, Virág Vas, Christina Eckl, Matthias Schiemann, Yi Zheng, Karin Dörr, Maria Carolina Florian, Hans A. Kestler, Kalpana Nattamai, Immanuel Andrä, Robert A.J. Oostendorp, Karin Scharffetter-Kochanek, Bettina Überle |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cellular differentiation Haploinsufficiency Biology Article Wnt-5a Protein Mice Animals Rejuvenation cdc42 GTP-Binding Protein Wnt Signaling Pathway Cellular Senescence Multidisciplinary Wnt signaling pathway Cell Polarity Cell Differentiation Hematopoietic Stem Cells Cell biology Mice Inbred C57BL Wnt Proteins Haematopoiesis Phenotype Cdc42 GTP-Binding Protein Ageing Immunology Female Stem cell Cell aging Adult stem cell |
| Zdroj: | Nature. 503(7476) |
| ISSN: | 1476-4687 |
| Popis: | 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 cells1,2. Ageing results in the inability of these tissuesto 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 elderly3–6. 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-intrinsicnon-canonical Wnt5a signalling in HSC ageing. |
| Databáze: | OpenAIRE |
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