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Wnt signaling balance regulates hematopoietic stem cell homeostasis


The role of noncanonical and canonical Wnt signaling in activating and expanding hematopoietic stem cells (HSCs) in vivo has not been described in detail. Sugimura et al. performed a series of elegant experiments to demonstrate that quiescent HSCs are maintained by the expression of Flamingo and Frizzled, two components of the noncanonical Wnt pathway.

The two interact closely; Flamingo regulates how Frizzled is distributed at the interface between HSCs and osteoblasts that express N-cadherin, a protein that enriches osteoprogenitor cells. When homeostasis is being maintained, N-cadherin+ osteoblasts express noncanonical Wnt ligands, which keep canonical Wnt signaling in check quite effectively. When the system is under stress, canonical Wnt signaling gains the upper hand, resulting in HSC activation.

The pathways involved are complex but the study suggests that Frizzled suppresses the Ca2+-NFAT- IFNγ pathway through the CDC42-CK1α complex. The findings go a long way to explaining previous contradictory results obtained by different international groups looking at HSC homeostasis.

Editor's comment: This study demonstrates that noncanonical Wnt signaling in N-cadherin-positive osteoblasts maintains quiescence of HSCs and antagonizes canonical Wnt signaling to activate HSCs. These observations provide important clues about how best to maintain or expand the use of HSCs in various disorders of hematopoiesis.

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