Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal

Adult hematopoietic stem/progenitor cell (HSPC) numbers remain stable in the absence of external stressors. After bone marrow (BM) transplant, HSPCs need to expand substantially to repopulate the BM and replenish the peripheral blood cell pool. In this study, we show that a noncanonical Wnt receptor, Frizzled-6 (Fzd6), regulates HSPC expansion and survival in a hematopoietic cell-intrinsic manner. Fzd6 deficiency increased the ratio of Flt3(hi) multipotent progenitors to CD150(+) stem cells in the mouse BM, suggesting defective stem cell maintenance. Competitive transplantation experiments demonstrated that Fzd6(-) (/) (-) HSPCs were able to home to the BM but were severely impaired in their capacity to reconstitute a lethally irradiated host. Lack of Fzd6 resulted in a strong activation of caspase-3 and a gradual loss of donor HSPCs and peripheral blood granulocytes. Fzd6 was also necessary for the efficient HSPC expansion during emergency hematopoiesis. Mechanistically, Fzd6 is a negative regulator of Cdc42 clustering in polarized cells. Furthermore, β-catenin-dependent signaling may be disinhibited in Fzd6(-) (/) (-) HSPCs. Collectively, our data reveal that Fzd6 has an essential role in HSPC maintenance and survival. Noncanonical Wnt-Fzd6 signaling pathway could thus present an interesting target for promoting HSPC expansion and multilineage hematopoietic recovery after transplant.