Open AccessHypoxic priming of mESCs accelerates vascular‐lineage differentiation through HIF1‐mediated inverse regulation of Oct4 and VEGF
Author(s) -
Lee SaeWon,
Jeong HanKyul,
Lee JiYoung,
Yang Jimin,
Lee Eun Ju,
Kim SuYeon,
Youn SeockWon,
Lee Jaewon,
Kim Woo Jean,
Kim KyuWon,
Lim Jeong Mook,
Park JongWan,
Park YoungBae,
Kim HyoSoo
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201101107
Subject(s) - embryoid body , microbiology and biotechnology , hypoxia (environmental) , embryonic stem cell , cellular differentiation , biology , vascular endothelial growth factor , priming (agriculture) , downregulation and upregulation , stem cell , endothelial stem cell , immunology , chemistry , induced pluripotent stem cell , cancer research , vegf receptors , in vitro , genetics , germination , botany , organic chemistry , gene , oxygen
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.