TY - JOUR
T1 - A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing
AU - Florian, Maria Carolina
AU - Nattamai, Kalpana J.
AU - Dörr, Karin
AU - Marka, Gina
AU - Überle, Bettina
AU - Vas, Virag
AU - Eckl, Christina
AU - Andrä, Immanuel
AU - Schiemann, Matthias
AU - Oostendorp, Robert A.J.
AU - Scharffetter-Kochanek, Karin
AU - Kestler, Hans Armin
AU - Zheng, Yi
AU - Geiger, Hartmut
N1 - Funding Information:
Acknowledgements We thank G. Van Zant and J. A. Cancelas for advice and critical reading of the manuscript. We thank F. Kirchhoff and D. van der Merwe for cell sorting support, A. Rück and the Institut für Lasertechnologien in der Medizin und Meßtechnik of Ulm University for support with confocal microscopy, and the Mouse and Cancer Core in Cincinnati and the Tierforschungszentrum of the University of Ulm for supporting our animal work. The work in the laboratory of H.G. is supported by grants from the Deutsche Forschungsgemeinschaft KFO 142, GE2063/1 and SFB 1074, the German Federal Ministry of Education and Research within its joint research project SyStaR (also to H.A.K. and K.S.-K.), the Excellence program of the Baden-Württemberg Foundation, the National Institute of Health, HL076604, DK077762 and AG040118, the Edward P. Evans foundation and the European Commission (FP7 Marie Curie Initial Training Network MARRIAGE). M.C.F. is supported by a ‘Bausteinprogramm’ of the Department of Medicine of Ulm University.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84888021623
U2 - 10.1038/nature12631
DO - 10.1038/nature12631
M3 - Article
C2 - 24141946
AN - SCOPUS:84888021623
SN - 0028-0836
VL - 503
SP - 392
EP - 396
JO - Nature
JF - Nature
IS - 7476
ER -