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O2 regulates stem cells through Wnt/β-catenin signalling

Nature Cell Biology volume 12, pages 1007–1013 (2010)Cite this article

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Abstract

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 cells1,2,3,4,5,6. 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 niche7. 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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Figure 1: Hypoxia activates Wnt/β-catenin signalling in mouse embryonic cells.
Figure 2: HIF-1 (HIF-1α/ARNT complex) mediates hypoxia-induced Wnt signalling in embryonic cells.
Figure 3: O2 regulation of Wnt/β-catenin signalling is differentiation-stage specific.
Figure 4: Deletion of Hif-1α in vivo suppresses adult hippocampal neurogenesis.
Figure 5: Neuronal Hif-1α regulates neurogenesis through Wnt/β-catenin signalling.

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Acknowledgements

We thank K. Kinzler and B. Vogelstein for the Wnt (TOP/FOP) reporter constructs; P. Carmeliet for Hif-1α−/− ES cells; and E. Brown for Ubc-Cre-ERT2 mice. We thank X. Sun, Case Western Reserve University, and H. Yu, University of Pennsylvania for technical assistance with tissue harvesting and sectioning. We thank B. Keith and the Simon lab for discussion and critical review of the manuscript. This work was supported by funds from the Howard Hughes Medical Institute (HHMI), the Abramson Family Cancer Research Institute, and the National Institutes of Health (Grant No. MH58324 to P.S.K). M.C.S. is an investigator of the HHMI.

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  1. Jolly Mazumdar

    Present address: Current address: Clinical Biomarkers, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.,

Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA

    Jolly Mazumdar & M. Celeste Simon

  2. Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA

    W. Timothy O'Brien & Peter S. Klein

  3. Division of Biological Sciences, U C San Diego, La Jolla, 92093, CA, USA

    Randall S. Johnson

  4. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, 44106, Ohio, USA

    Joseph C. LaManna

  5. Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, 19426, PA, USA

    Juan C. Chavez

  6. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Jolly Mazumdar & M. Celeste Simon

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Contributions

J.M. and W.T.O. designed, performed and analysed the experiments; P.S.K and M.C.S assisted in the interpretation of results; J.C.C. and J.C.L. provided the αCamKII-Cre- Hif-1αf/f mice; R.S.J. provided the Hif-1αf/f mice; J.M. made the figures and wrote the paper; M.C.S. edited the paper.

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Correspondence to M. Celeste Simon.

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The authors declare no competing financial interests.

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Mazumdar, J., O'Brien, W., Johnson, R. et al. O2 regulates stem cells through Wnt/β-catenin signalling. Nat Cell Biol 12, 1007–1013 (2010). https://doi.org/10.1038/ncb2102

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