Making a Point with Wnt Signals

Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
Science (Impact Factor: 33.61). 03/2013; 339(6126):1388-9. DOI: 10.1126/science.1236641
Source: PubMed


Embryonic stem cell division is influenced by the spatial orientation of the cells relative to the source of Wnt protein.

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    • "Habib et al. recently showed that a localized signal of the Wnt signaling agonist Wnt3A in mESCs results in asymmetric inheritance of pluripotency following cell division (Habib et al., 2013). However, global stimulation of noncanonical Wnt signaling by Wnt5A rescued the asymmetric effect of the local Wnt3A signal (Berndt and Moon, 2013; Habib et al., 2013). Therefore, we speculated that the application of Wnt5A could have a positive effect on hESC FIG. 1. Origin of mESCs and mEpiSCs, in relation to hESCs. "
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    ABSTRACT: In mice, inhibition of both the fibroblast growth factor (FGF) mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/Erk) and the Wnt signaling inhibitor glycogen synthase-3β (GSK3β) enables the derivation of mouse embryonic stem cells (mESCs) from nonpermissive strains in the presence of leukemia inhibitory factor (LIF). Whereas mESCs are in an uncommitted naïve state, human embryonic stem cells (hESCs) represent a more advanced state, denoted as primed pluripotency. This burdens hESCs with a series of characteristics, which, in contrast to naïve ESCs, makes them not ideal for key applications such as cell-based clinical therapies and human disease modeling. In this study, different small molecule combinations were applied during human ESC derivation. Hereby, we aimed to sustain the naïve pluripotent state, by interfering with various key signaling pathways. First, we tested several combinations on existing, 2i (PD0325901 and CHIR99021)-derived mESCs. All combinations were shown to be equally adequate to sustain the expression of naïve pluripotency markers. Second, these conditions were tested during hESC derivation. Overall, the best results were observed in the presence of medium supplemented with 2i, LIF, and the noncanonical Wnt signaling agonist Wnt5A, alone and combined with epinephrine. In these conditions, outgrowths repeatedly showed an ESC progenitor-like morphology, starting from day 3. Culturing these "progenitor cells" did not result in stable, naïve hESC lines in the current conditions. Although Wnt5A could not promote naïve hESC derivation, we found that it was sustaining the conversion of established hESCs toward a more naïve state. Future work should aim to distinct the effects of the various culture formulations, including our Wnt5A-supplemented medium, reported to promote stable naïve pluripotency in hESCs.
    06/2015; 17(3):170-180. DOI:10.1089/cell.2014.0085

  • 03/2013; 6(268):ec76-ec76. DOI:10.1126/scisignal.2004170
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    ABSTRACT: Wnt signaling pathway plays an important role in physiological and pathological process, including in the occurrence and development of tumor. The purpose of this study is to determine whether Wnt2 and sFRP4, key molecules of signaling pathway, are of prognostic value for survival in patients with pancreatic cancer. We performed immunohistochemistry on tissue microarrays containing 90 pancreatic cancer specimens to evaluate the protein expression of Wnt2 and sFRP4. Our results showed that the cytoplasmic expression level of Wnt2 in pancreatic cancer tissues was significantly associated with LNM (P=0.029) and AJCC stage (P=0.008). Additionally, Kaplan-Meier analysis indicated that high Wnt2 expression was significantly correlated with poor clinical outcomes of patients with pancreatic cancer. In conclusion, Wnt2 may play an important role in the development of pancreatic cancer through activation of the Wnt pathways and serve as a potential candidate for treatment target of pancreatic cancer.
    American Journal of Cancer Research 09/2014; 4(5):537-44. · 4.17 Impact Factor
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