The Signaling Protein Wnt4 Enhances Thymopoiesis and Expands Multipotent Hematopoietic Progenitors through β-Catenin-Independent Signaling

SummaryDespite 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+Kithi 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 β-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 (β-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.