Noncanonical Wnt Signaling Maintains Hematopoietic Stem Cells in the Niche

Abstract

SUMMARY Wnt 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.

Leucine-rich Repeat-containing G-protein-coupled Receptor 5 Marks Short-term Hematopoietic Stem and Progenitor Cells during Mouse Embryonic Development

“…The volume of the formalin was at least 10 times that of the embryos. For immunostaining, we followed procedures reported previously (23,24). Sections were incubated; Anti-GFP and anti-Ki67 were added to the tissue section slides.…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…Another critical question is whether the Wnt-independent functions of b-catenin and/or b-catenin-independent functions of Wnt signaling contribute to the complexities of stem cell regulation. Superimposed on these issues is the increasing evidence that noncanonical Wnt pathways can powerfully influence stem cell behavior ranging from the roles of PCP in symmetric cell divisions of muscle satellite stem cells (Le Grand et al 2009) to roles for noncanonical Wnt signaling in the hematopoietic stem cell niche as well as its aging counterparts (Sugimura et al 2012;Florian et al 2013). Whether these pathways compete for shared components such as the Dvl proteins and whether there are feedback circuitries that affect the regulation of these Wnt pathways will no doubt provide plenty of fuel for future investigations.…”

The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

“…21 However, the non-canonical Wnt pathway was reported to inhibit canonical Wnt signaling in HSC and increased the numbers of short-term (ST-HSC) and long-term HSC (LT-HSC) populations by maintaining HSC in a quiescent G0 state. 22,24,25 Both the canonical and non-canonical Wnt pathways can induce BM-derived tolerogenic DC induced by GM-CSF and IL-4 (GM-DC). 26 Activation of the canonical Wnt signaling pathway during Flt3L-induced DC (FL-DC) differentiation resulted in a significant increase in the proportion of conventional CD11c 1 CD11b 1 B220 2 DC, and the proportion of CD11c 1 CD11b 2 B220 1 pDC was dramatically reduced.…”

“…19,20 The Wnt signaling pathways have been implicated as the signaling cascades involved in the regulation of hematopoietic stem cell (HSC) function and other stages during hematopoiesis. 21,22 Hematopoiesis proceeds in a stepwise manner from primordial long-term (LT)-HSCs that give rise to short-term (ST)-HSCs; in turn, (ST)-HSC can differentiate into a multipotent progenitor (MPP) population. 23 The canonical Wnt signaling pathway has been demonstrated to regulate the differentiation of HSC, myeloid precursors, and T lymphoid precursors during hematopoiesis in a dose-dependent manner.…”