title: A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing.
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.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Florian
authors.forename: Kalpana J
authors.initials: KJ
authors.lastname: Nattamai
authors.forename: Karin
authors.initials: K
authors.lastname: Dörr
authors.forename: Gina
authors.initials: G
authors.lastname: Marka
authors.forename: Bettina
authors.initials: B
authors.lastname: Uberle
authors.forename: Virag
authors.initials: V
authors.lastname: Vas
authors.forename: Christina
authors.initials: C
authors.lastname: Eckl
authors.forename: Immanuel
authors.initials: I
authors.lastname: Andrä
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.forename: Hans Armin
authors.initials: HA
authors.lastname: Kestler
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity; D016922:Cellular Senescence; D005260:Female; D057895:Haploinsufficiency; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012060:Rejuvenation; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C581598:Cdc42 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020764:cdc42 GTP-Binding Protein