title: Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal.
abstract: Adult hematopoietic stem/progenitor cell (HSPC) numbers remain stable in the absence of external stressors. After bone marrow (BM) transplant, HSPCs need to expand substantially to repopulate the BM and replenish the peripheral blood cell pool. In this study, we show that a noncanonical Wnt receptor, Frizzled-6 (Fzd6), regulates HSPC expansion and survival in a hematopoietic cell-intrinsic manner. Fzd6 deficiency increased the ratio of Flt3(hi) multipotent progenitors to CD150(+) stem cells in the mouse BM, suggesting defective stem cell maintenance. Competitive transplantation experiments demonstrated that Fzd6(-) (/) (-) HSPCs were able to home to the BM but were severely impaired in their capacity to reconstitute a lethally irradiated host. Lack of Fzd6 resulted in a strong activation of caspase-3 and a gradual loss of donor HSPCs and peripheral blood granulocytes. Fzd6 was also necessary for the efficient HSPC expansion during emergency hematopoiesis. Mechanistically, Fzd6 is a negative regulator of Cdc42 clustering in polarized cells. Furthermore, β-catenin-dependent signaling may be disinhibited in Fzd6(-) (/) (-) HSPCs. Collectively, our data reveal that Fzd6 has an essential role in HSPC maintenance and survival. Noncanonical Wnt-Fzd6 signaling pathway could thus present an interesting target for promoting HSPC expansion and multilineage hematopoietic recovery after transplant.
authors.affiliation: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
authors.forename: Belma Melda
authors.initials: BM
authors.lastname: Abidin
authors.affiliation: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Owusu Kwarteng
authors.affiliation: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada krista.heinonen@iaf.inrs.ca.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Heinonen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005434:Flow Cytometry; D051157:Frizzled Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
chemical_list: C581598:Cdc42 protein, mouse; D051157:Frizzled Receptors; C111048:Fzd6 protein, mouse; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein