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  • Whatever the exact mechanism it is clear

    2018-10-26

    Whatever the exact mechanism, it is clear that Wnt signaling levels need to be strictly controlled. It is well possible that somewhat higher Wnt levels, which are detrimental to stemness, can be tolerated if HSC survival is enhanced, which then would lead to better self-renewal at this somewhat higher Wnt signaling dose. For instance PI3K/Akt signaling (Perry et al., 2011), as well as expression of Bcl2 (Reya et al., 2003) can provide such signals. Apparently, high Wnt signaling levels can be tolerated in HSC in combination with activation of other survival pathways. Intriguingly, the high Wnt levels in combination with oncogene activation in acute myeloid leukemia seem to allow the Wnt pathway to function as a self-renewal factor for leukemic stem over at this website (Wang et al., 2010), whereas high Wnt levels cannot do so in normal HSCs. The different localization of normal versus malignant HSCs in the bone marrow niche (Lane et al., 2011) may also contribute to this differential outcome of high Wnt dosage and opens up a therapeutic window targeting leukemic but not normal stem cells.
    Experimental Procedures
    Acknowledgments We thank Edwin de Haas for expert cell sorting and Paul Roozen for initiating this project. We thank Bjorn Clausen for help with the constitutive activated β-catenin allele. This work was supported in part by a TOP grant from The Netherlands Organization for Health Research and Development (ZonMw Project 40-00812-98-09050), a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant no. FES0908), and JSH/EHA fellowship to M.H.B.
    Introduction Epithelial integrity and tissue homeostasis are severely challenged by wounding or a range of pathological states. Under such conditions, epithelial cells can detach from the underlying basement membrane and undergo apoptotic cell death through a process known as anoikis (Chiarugi and Giannoni, 2008; Frisch and Francis, 1994; Frisch and Screaton, 2001; Taddei et al., 2012). Subsequently, the missing epithelial cells can be replaced through the activity of endogenous stem/progenitor cells. In the prostate, insults such as bacterial or viral infection can result in inflammation and epithelial cell death, but the process of repair has been poorly studied to date. The identity of epithelial stem/progenitor cells within the prostate remains a subject of intense study (Shibata and Shen, 2015). The prostate epithelium comprises luminal, basal, and neuroendocrine cells, with both luminal and basal compartments containing stem/progenitor activity (Shen and Abate-Shen, 2010). In addition, rare “intermediate” cells that co-express basal and luminal markers have been proposed to correspond to stem/progenitor cells (De Marzo et al., 1998; Verhagen et al., 1988; Wang et al., 2001; Xue et al., 1998), or a transitional state between basal progenitors and luminal descendants (Bonkhoff and Remberger, 1996; Litvinov et al., 2006; Ousset et al., 2012; van Leenders et al., 2000). Stem/progenitor activity has been observed in distinct contexts during prostate development and homeostasis in vivo. In the hormonally naive adult prostate epithelium, luminal and basal compartments are maintained by unipotent progenitors (Choi et al., 2012; Lu et al., 2013; Wang et al., 2013), while during prostate organogenesis some basal progenitors are multipotent, giving rise to luminal and neuroendocrine progeny (Ousset et al., 2012; Wang et al., 2014a). In addition, rare bipotential populations exist within both the luminal and basal compartments during androgen-mediated regeneration of the regressed prostate (Lee et al., 2014; Wang et al., 2009, 2013, 2015). In contrast, both luminal and basal populations display considerable lineage plasticity in specific contexts. Explanted luminal cells can generate basal cells in organoid culture (Chua et al., 2014; Karthaus et al., 2014), whereas basal cells can generate luminal cells in sphere formation assays, and after recombination with embryonic urogenital mesenchyme in renal grafts (Burger et al., 2005; Goldstein et al., 2008, 2010; Hofner et al., 2015; Lawson et al., 2007; Richardson et al., 2004; Wang et al., 2013). Basal-to-luminal differentiation can also occur in pathological contexts, such as during prostate cancer initiation (Choi et al., 2012; Lu et al., 2013; Wang et al., 2013, 2014b), and after acute inflammation in bacterial prostatitis (Kwon et al., 2014b).