Non-Canonical Wnt Signaling Maintains Hematopoietic Stem Cell Through Flamingo and Frizzled8 Interaction in the Niche

Sugimura, Ryohichi (2012). Non-Canonical Wnt Signaling Maintains Hematopoietic Stem Cell Through Flamingo and Frizzled8 Interaction in the Niche. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f0eb

Abstract

Wnt signaling is involved in self-renewal and maintenance of hematopoietic stem cells (HSCs); however, the particular role of non-canonical Wnt signaling in regulating HSCs in vivo is largely unknown. Here I show Flamingo and Frizzled8, members of non-canonical Wnt signaling, both express in and functionally maintain quiescent long-term HSCs. Flamingo regulates Frizzled8 distribution at the interface between HSCs and N-cadherin+ osteoblasts (N-cad+OBs that enrich osteoprogenitors) in the niche. I further show that N-cad+OBs predominantly express non-canonical Wnt ligands and inhibitors of canonical Wnt signaling under homeostasis. This non-canonical Wnt signaling is attenuated prior to activation of HSCs. In the activated HSCs, however, canonical Wnt signaling is enhanced. Mechanistically, non-canonical Wnt signaling mediated by Frizzled8 suppresses the Ca²⁺-NFAT-IFNγ pathway and antagonizes canonical Wnt signaling in HSCs. My findings demonstrate that non-canonical Wnt signaling maintains quiescent longterm HSCs through Flamingo and Frizzled8 interaction in the niche.