title: High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells.
abstract: Canonical Wnt signaling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signaling has been the subject of much debate but there is consensus that high Wnt signals lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in hematopoietic stem cells (HSCs) and performed whole-genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels, enhanced differentiation, and diminished proliferation but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signaling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 Leiden, the Netherlands.
authors.forename: Farbod
authors.initials: F
authors.lastname: Famili
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 Leiden, the Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Brugman
authors.affiliation: Department of Clinical Genetics, VU University, 1081 Amsterdam, the Netherlands.
authors.forename: Erdogan
authors.initials: E
authors.lastname: Taskesen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 Leiden, the Netherlands.
authors.forename: Brigitta E A
authors.initials: BEA
authors.lastname: Naber
authors.affiliation: Department of Pathology, Erasmus Medical Center, 3000 Rotterdam, the Netherlands.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 Leiden, the Netherlands. Electronic address: f.j.t.staal@lumc.nl.
authors.forename: Frank J T
authors.initials: FJT
authors.lastname: Staal
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C000613192:adenomatous polyposis coli protein, mouse