These authors contributed equally to this work.
Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF
Article first published online: 23 JUL 2012
Copyright © 2012 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 4, Issue 9, pages 924–938, September 2012
How to Cite
Lee, S.-W., Jeong, H.-K., Lee, J.-Y., Yang, J., Lee, E. J., Kim, S.-Y., Youn, S.-W., Lee, J., Kim, W. J., Kim, K.-W., Lim, J. M., Park, J.-W., Park, Y.-B. and Kim, H.-S. (2012), Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF. EMBO Mol Med, 4: 924–938. doi: 10.1002/emmm.201101107
- Issue published online: 4 SEP 2012
- Article first published online: 23 JUL 2012
- Manuscript Accepted: 18 MAY 2012
- Manuscript Revised: 15 MAY 2012
- Manuscript Received: 28 NOV 2011
- Innovative Research Institute for Cell Therapy. Grant Number: A062260
- National Research Foundation. Grant Number: (MEST) (2010-0020257
- embryoid bodies;
- endothelial cells;
- mesoderm differentiation;
- mouse embryonic stem cells;
Hypoxic microenvironment plays an important role in determining stem cell fates. However, it is controversial to which direction between self-renewal and differentiation the hypoxia drives the stem cells. Here, we investigated whether a short exposure to hypoxia (termed ‘hypoxic-priming’) efficiently directed and promoted mouse embryonic stem cells (mESCs) to differentiate into vascular-lineage. During spontaneous differentiation of embryoid bodies (EBs), hypoxic region was observed inside EB spheroids even under normoxic conditions. Indeed, hypoxia-primed EBs more efficiently differentiated into cells of vascular-lineage, than normoxic EBs did. We found that hypoxia suppressed Oct4 expression via direct binding of HIF-1 to reverse hypoxia-responsive elements (rHREs) in the Oct4 promoter. Furthermore, vascular endothelial growth factor (VEGF) was highly upregulated in hypoxia-primed EBs, which differentiated towards endothelial cells in the absence of exogenous VEGF. Interestingly, this differentiation was abolished by the HIF-1 or VEGF blocking. In vivo transplantation of hypoxia-primed EBs into mice ischemic limb elicited enhanced vessel differentiation. Collectively, our findings identify that hypoxia enhanced ESC differentiation by HIF-1-mediated inverse regulation of Oct4 and VEGF, which is a novel pathway to promote vascular-lineage differentiation.