Noncanonical Wnt Signaling Maintains Hematopoietic Stem Cells in the Niche

SummaryWnt signaling is involved in self-renewal and maintenance of hematopoietic stem cells (HSCs); however, the particular role of noncanonical Wnt signaling in regulating HSCs in vivo is largely unknown. Here, we show Flamingo (Fmi) and Frizzled (Fz) 8, members of noncanonical Wnt signaling, both express in and functionally maintain quiescent long-term HSCs. Fmi regulates Fz8 distribution at the interface between HSCs and N-cadherin+ osteoblasts (N-cad+OBs that enrich osteoprogenitors) in the niche. We further found that N-cad+OBs predominantly express noncanonical Wnt ligands and inhibitors of canonical Wnt signaling under homeostasis. Under stress, noncanonical Wnt signaling is attenuated and canonical Wnt signaling is enhanced in activation of HSCs. Mechanistically, noncanonical Wnt signaling mediated by Fz8 suppresses the Ca2+-NFAT- IFNγ pathway, directly or indirectly through the CDC42-CK1α complex and also antagonizes canonical Wnt signaling in HSCs. Taken together, our findings demonstrate that noncanonical Wnt signaling maintains quiescent long-term HSCs through Fmi and Fz8 interaction in the niche.

Graphical AbstractFigure optionsDownload high-quality image (362 K)Download as PowerPoint slideHighlights
► Flamingo regulates Frizzled8 between HSC and N-cadherin+ osteoblast (N-cad+OB)
► N-cad+OBs and HSCs maintain noncanonical Wnt signaling in homeostasis
► Flamingo and Frizzled8 functionally maintain quiescent long-term HSCs
► Noncanonical Wnt signaling suppresses NFAT pathway and canonical Wnt signaling