The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions
Open accessAbstract
Human embryonic stem (hES) cells are routinely cultured under atmospheric, 20% oxygen tensions but are derived from embryos which reside in a 3–5% oxygen (hypoxic) environment. Maintenance of oxygen homeostasis is critical to ensure sufficient levels for oxygen-dependent processes. This study investigates the importance of specific hypoxia inducible factors (HIFs) in regulating the hypoxic responses of hES cells. We report that culture at 20% oxygen decreased hES cell proliferation and resulted in a significantly reduced expression of SOX2, NANOG and POU5F1 (OCT4) mRNA as well as POU5F1 protein compared with hypoxic conditions. HIF1A protein was not expressed at 20% oxygen and displayed only a transient, nuclear localisation at 5% oxygen. HIF2A (EPAS1) and HIF3A displayed a cytoplasmic localisation during initial hypoxic culture but translocated to the nucleus following long-term culture at 5% oxygen and were significantly upregulated compared with cells cultured at 20% oxygen. Silencing of HIF2A resulted in a significant decrease in both hES cell proliferation and POU5F1, SOX2 and NANOG protein expression while the early differentiation marker, SSEA1, was concomitantly increased. HIF3A upregulated HIF2A and prevented HIF1A expression with the knockdown of HIF3A resulting in the reappearance of HIF1A protein. In summary, these data demonstrate that a low oxygen tension is preferential for the maintenance of a highly proliferative, pluripotent population of hES cells. While HIF3A was found to regulate the expression of both HIF1A and HIF2A, it is HIF2A which regulates hES cell pluripotency as well as proliferation under hypoxic conditions.
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Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 1×
“However, the contribution of HIF2A and HIF3A, which are believed to be regulated in a similar manner (Ivan et al. 2001, Masson et al. 2001), remain to be fully characterised.”
BackgroundHuang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7987 · Cited by 2,113
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
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Derivation of human embryonic stem cells in defined conditions
Ludwig, T. E., Levenstein, M. E., Jones, J. M., Berggren, W. T., Mitchen, E. R., Frane, J. L., Crandall, L. J., Daigh, C. A., Conard, K. R., Piekarczyk, M. S., et al. (2006) · Nature Biotechnology · doi:10.1038/nbt1177 · Cited by 1,114
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“However, the contribution of HIF2A and HIF3A, which are believed to be regulated in a similar manner (Ivan et al. 2001, Masson et al. 2001), remain to be fully characterised.”
BackgroundHypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30117 · Cited by 596
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Maynard, M. A., Qi, H., Chung, J., Lee, E. H. L., Kondo, Y., Hara, S., Conaway, R. C., Conaway, J. W., & Ohh, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208681200 · Cited by 283
Cited by
Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment
Huang, G., Li, F., Zhao, X., Ma, Y., Li, Y., Lin, M., Jin, G., Lu, T. J., Genin, G. M., & Xu, F. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00094 · Cited by 825
Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts
Varum, S., Rodrigues, A. S., Moura, M. B., Momcilovic, O., Easley, C. A., Ramalho-Santos, J., Van Houten, B., & Schatten, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020914 · Cited by 671
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641
Lopaschuk, G. D., & Jaswal, J. S. (2010) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181e74a14 · Cited by 636
Ravenna, L., Salvatori, L., & Russo, M. A. (2016) · The FEBS Journal · doi:10.1111/febs.13572 · Cited by 97
Metadata
- Authors
- Forristal, C. E., Wright, K. L., Hanley, N. A., Oreffo, R. O. C., & Houghton, F. D.
- Venue
- Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-01-01
- Volume
- 139
- Issue
- 1
- Pages
- 85-97
- ISSN
- 1470-1626 (ISSN-L)
- 1741-7899
- OpenAlex
- W1972782503
- Cited by
- 396
- References
- 11
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
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