O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Nature Cell Biology (Impact Factor: 19.68). 10/2010; 12(10):1007-13. DOI: 10.1038/ncb2102
Source: PubMed


Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (<5% O2) have revealed strong regulatory links between O2 availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O2 gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1α (HIF-1α), a principal mediator of hypoxic adaptations, modulates Wnt/β-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing β-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/β-catenin activity is closely associated with low O2 regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1α deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/β-catenin signalling in the subgranular zone. O2 availability, therefore, may have a direct role in stem cell regulation through HIF-1α modulation of Wnt/β-catenin signalling.

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    • "In colon carcinoma lines, hypoxia (1% O2) causes HIF-1α, the major regulator of the transcriptional response to hypoxia [37], [38], [39], to compete with TCF-4 for binding to β-catenin; this causes an increase in HIF-1α-mediated transcription while decreasing TCF-4 mediated transcription [40], which the authors suggest promote survival and adaptation to hypoxia and contribute to the cell cycle arrest induced by hypoxia, respectively. In contrast to its effect on differentiated cells, hypoxia, acting via HIF-1α, has been reported to enhance canonical Wnt signaling in embryonic stem cells and neural stem cells, promoting stem cell proliferation and Wnt-regulated differentiation [41], [42]. In this work, we demonstrate a new mechanism of hypoxia adaptation, involving Wnt pathway activation, which promotes hypoxia tolerance during fly development. "
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    ABSTRACT: Adaptation to hypoxia, defined as a condition of inadequate oxygen supply, has enabled humans to successfully colonize high altitude regions. The mechanisms attempted by organisms to cope with short-term hypoxia include increased ATP production via anaerobic respiration and stabilization of Hypoxia Inducible Factor 1α (HIF-1α). However, less is known about the means through which populations adapt to chronic hypoxia during the process of development within a life time or over generations. Here we show that signaling via the highly conserved Wnt pathway impacts the ability of Drosophila melanogaster to complete its life cycle under hypoxia. We identify this pathway through analyses of genome sequencing and gene expression of a Drosophila melanogaster population adapted over >180 generations to tolerate a concentration of 3.5-4% O2 in air. We then show that genetic activation of the Wnt canonical pathway leads to increased rates of adult eclosion in low O2. Our results indicate that a previously unsuspected major developmental pathway, Wnt, plays a significant role in hypoxia tolerance.
    PLoS ONE 08/2014; 9(8):e103292. DOI:10.1371/journal.pone.0103292 · 3.23 Impact Factor
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    • "Our present findings supported those of previous studies, suggesting that MSCs cultured under HBO undergo increased differentiation into osteogenic cells by up-regulating Runx2 expression (Figure 1A). Because oxygen availability regulates stem cells via Wnt/β-catenin signaling [23], we intended to examine the molecular mechanisms involved after HBO treatment by assessing the Wnt/β-catenin pathway. Our data showed that the levels of Wnt3a, β-catenin, and Runx2 were upregulated, while GSK-3β was downregulated after HBO treatment. "
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    ABSTRACT: Hyperbaric oxygenation was shown to increase bone healing in a rabbit model. However, little is known about the regulatory factors and molecular mechanism involved.We hypothesized that the effect of hyperbaric oxygen (HBO) on bone formation is mediated via increases in the osteogenic differentiation of mesenchymal stem cells (MSCs) which are regulated by Wnt signaling. The phenotypic characterization of the MSCs was analyzed by flow cytometric analysis. To investigate the effects of HBO on Wnt signaling and osteogenic differentiation of MSCs, mRNA and protein levels of Wnt3a, beta-catenin, GSK-3beta, Runx 2, as well as alkaline phosphatase activity, calcium deposition, and the intensity of von Kossa staining were analyzed after HBO treatment. To investigate the effects of HBO on Wnt processing and secretion, the expression of Wntless and vacuolar ATPases were quantified after HBO treatment. Cells expressed MSC markers such as CD105, CD146, and STRO-1. The mRNA and protein levels of Wnt3a, beta-catenin, and Runx 2 were up-regulated, while GSK-3beta was down-regulated after HBO treatment. Western blot analysis showed an increased beta-catenin translocation with a subsequent stimulation of the expression of target genes after HBO treatment. The above observation was confirmed by small interfering (si)RNA treatment. HBO significantly increased alkaline phosphatase activity, calcium deposition, and the intensity of von Kossa staining of osteogenically differentiated MSCs. We further showed that HBO treatment increased the expression of Wntless, a retromer trafficking protein, and vacuolar ATPases to stimulate Wnt processing and secretion, and the effect was confirmed by siRNA treatment. HBO treatment increased osteogenic differentiation of MSCs via regulating Wnt processing, secretion, and signaling.
    BMC Musculoskeletal Disorders 02/2014; 15(1):56. DOI:10.1186/1471-2474-15-56 · 1.72 Impact Factor
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    • "It has been shown that exposure to low oxygen concentrations (or hypoxia) can stimulate the proliferation and differentiation of cultured embryonic and adult NSCs (Vieira et al., 2011). This effect has been associated with β-catenin (Mazumdar et al., 2010; Cui et al., 2011), a key component of the Wnt/β-catenin signaling pathway. "
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    ABSTRACT: Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6-72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer's disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.
    Frontiers in Cellular Neuroscience 02/2014; 8:17. DOI:10.3389/fncel.2014.00017 · 4.29 Impact Factor
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