한빛사논문
- 조회3,359
Abstract
Sae-Won Lee1,†, Han-Kyul Jeong1,†, Ji-Young Lee1, Jimin Yang1, Eun Ju Lee1, Su-Yeon Kim1, Seock-Won Youn1, Jaewon Lee1, Woo Jean Kim2, Kyu-Won Kim3,4, Jeong Mook Lim5, Jong-Wan Park6, Young-Bae Park1, Hyo-Soo Kim1,4,*
1Department of Internal Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
2National Research Laboratory of Regenerative Sexual Medicine, Department of Urology, Inha University School of Medicine, Incheon, Korea
3Division of Pharmaceutical Biosciences, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
4WCU Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea
5WCU Biomodulation Program, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea
6Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea
†These authors contributed equally to this work.
*To whom correspondence may be addressed
Keywords:embryoid bodies;endothelial cells;mesoderm differentiation;mouse embryonic stem cells;niche
Abstract
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.
논문정보
- Research article
- 2012년 07월 (BRIC 등록일 )
- 국내 연구진
- 의약학 > 응용의학
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