The signaling protein Wnt4 enhances thymopoiesis and expands multipotent hematopoietic progenitors through beta-catenin-independent signaling.
Despite studies based on deletion or activation of intracellular components of the canonical Wingless related (Wnt) pathway, the role of Wnts in hematolymphopoiesis remains controversial. Using gain-of-function and loss-of-function models, we found that Wnt4 differentially affected diverse subsets of hematopoietic stem and progenitor cells. Bone-marrow and thymic Lin(-)Sca1(+)Kit(hi) cells (LSKs) were the key targets of Wnt4. In adult mice, Wnt4-induced expansion of Flt3(+) bone-marrow LSKs (lymphoid-primed multipotent progenitors) led to a sizeable accumulation of the most immature thymocyte subsets (upstream of beta-selection) and a major increase in thymopoiesis. Conversely, Wnt4(-/-) neonates showed low frequencies of bone-marrow LSKs and thymic hypocellularity. We provide compelling evidence that Wnt4 activates noncanonical (beta-catenin-independent) signaling and that its effects on hematopoietic cells are mainly non-cell-autonomous. Our work shows that Wnt4 overexpression has a unique ability to expand Flt3(+) LSKs in adults and demonstrates that noncanonical Wnt signaling regulates thymopoiesis.
Louis
Isabelle
I
Institute for Research in Immunology and Cancer and, Université de Montréal, Montreal, QC H3C 3J7, Canada.
Heinonen
Krista M
KM
Chagraoui
Jalila
J
Vainio
Seppo
S
Sauvageau
Guy
G
Perreault
Claude
C
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000276:immunology; D051153:Wnt Proteins / Q000276:immunology / Q000378:metabolism*; D060528:Wnt4 Protein; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism*
D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin