title: Discrete roles of canonical and non-canonical Wnt signaling in hematopoiesis and lymphopoiesis.
abstract: The mechanisms that regulate proliferation, fate decisions and differentiation of hematopoietic stem cells (HSC) and thymic stem cells are highly complex. Several signaling pathways including Wnt signaling have important roles during these processes. Both canonical and non-canonical Wnt signaling are important in normal and malignant hematopoiesis and lymphoid development, yet their precise roles are controversial. In a side-by-side comparison, we investigated the roles of the canonical and non-canonical Wnt pathway in hematopoiesis and thymopoiesis. As complete loss-of-function models for non-canonical Wnt signaling are not yet available and highly complex for canonical Wnt signaling, we decided to use a gain-of-function approach. To this end, Wnt3a and Wn5a, two well-known prototypical canonical and non-canonical Wnt ligands were produced in hematopoiesis supporting stromal assays. High levels of Wnt3a signaling blocked T-cell development at early stages, whereas intermediate levels accelerated T-cell development. In contrast, Wnt5a signaling prompted apoptosis in developing thymocytes, without affecting differentiation at a particular stage. To explore the role of Wnt3a and Wnt5a in vivo, we transduced HSCs isolated from fetal liver, transduced with Wnt3a and Wnt5a vectors, and performed reconstitution assays in irradiated C57Bl/6 mice. Wnt3a overexpression led to increased lymphopoiesis, whereas Wnt5a augments myelopoiesis in the bone marrow (BM) and spleen. Thus, the canonical and non-canonical Wnt signaling have discrete roles in hematopoiesis and thymopoiesis, and understanding their right dose of action is crucial for prospective translational applications.
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Famili
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: B A E
authors.initials: BA
authors.lastname: Naber
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Vloemans
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E F E
authors.initials: EF
authors.lastname: de Haas
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Tiemessen
authors.affiliation: Department of Immunohematology and Blood Transfusion (IHB), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F J T
authors.initials: FJ
authors.lastname: Staal
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C555510:WNT3A protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C438615:Wnt5a protein, mouse