title: Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation.
abstract: Canonical Wnt signaling has been implicated in various aspects of hematopoiesis. Its role is controversial due to different outcomes between various inducible Wnt-signaling loss-of-function models and also compared with gain-of-function systems. We therefore studied a mouse deficient for a Wnt gene that seemed to play a nonredundant role in hematopoiesis. Mice lacking Wnt3a die prenatally around embryonic day (E) 12.5, allowing fetal hematopoiesis to be studied using in vitro assays and transplantation into irradiated recipient mice. Here we show that Wnt3a deficiency leads to a reduction in the numbers of hematopoietic stem cells (HSCs) and progenitor cells in the fetal liver (FL) and to severely reduced reconstitution capacity as measured in secondary transplantation assays. This deficiency is irreversible and cannot be restored by transplantation into Wnt3a competent mice. The impaired long-term repopulation capacity of Wnt3a(-/-) HSCs could not be explained by altered cell cycle or survival of primitive progenitors. Moreover, Wnt3a deficiency affected myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation. Our results show that Wnt3a signaling not only provides proliferative stimuli, such as for immature thymocytes, but also regulates cell fate decisions of HSC during hematopoiesis.
authors.affiliation: Department of Immunology, ErasmusMC, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Luis
authors.forename: Floor
authors.initials: F
authors.lastname: Weerkamp
authors.forename: Brigitta A E
authors.initials: BA
authors.lastname: Naber
authors.forename: Miranda R M
authors.initials: MR
authors.lastname: Baert
authors.forename: Edwin F E
authors.initials: EF
authors.lastname: de Haas
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.forename: Sjanneke
authors.initials: S
authors.lastname: Heuvelmans
authors.forename: Ronald R
authors.initials: RR
authors.lastname: De Krijger
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse