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

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 2/2 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, b-catenin–dependent signaling may be disinhibited in Fzd6 2/2 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. A dult hematopoietic stem/progenitor cells (HSPCs) are maintained in a specialized niche in the bone marrow (BM). Multiple signals from the niche regulate HSPC numbers and their ability to self-renew as well as to differentiate into all blood cell types (1, 2). Microenvironmental cues also influence the cell-cycle status of HSPCs and modulate stem cell polarity. Polarity has been suggested to maintain the dynamic balance of HSPC pool by regulating the outcome (self-renewal versus differentiation) of HSPC divisions (3–6). The molecular mechanisms coordinating the cross-talk between niche-associated signals and HSPC-intrinsic polarity determinants remain unclear. Wnt signaling is necessary for adult HSPC self-renewal in the BM, but it needs to be tightly regulated (7–9): mild increases in b-catenin–dependent signaling enhance HSPC function, whereas stronger signals would favor myeloid expansion to the detriment of stem cell self-renewal. Although noncanonical, b-catenin–in-dependent, Wnt signaling pathways are known to modulate cell polarity, cell motility, and tissue patterning (10–17), their role in hematopoietic cells is much less well established. Exogenous Wnt5a has been shown to activate b-catenin–independent sig-naling in Lin 2 Sca1 + c-Kit hi (LSK) hematopoietic progenitors and to improve HSPC maintenance and function by promoting their quiescence (18–21). By contrast, hematopoietic Wnt5a expression is …