title: Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF.
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.
authors: Department of Internal Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Korea.
authors: Sae-Won
authors: SW
authors: Lee
authors: Han-Kyul
authors: HK
authors: Jeong
authors: Ji-Young
authors: JY
authors: Lee
authors: Jimin
authors: J
authors: Yang
authors: Eun Ju
authors: EJ
authors: Lee
authors: Su-Yeon
authors: SY
authors: Kim
authors: Seock-Won
authors: SW
authors: Youn
authors: Jaewon
authors: J
authors: Lee
authors: Woo Jean
authors: WJ
authors: Kim
authors: Kyu-Won
authors: KW
authors: Kim
authors: Jeong Mook
authors: JM
authors: Lim
authors: Jong-Wan
authors: JW
authors: Park
authors: Young-Bae
authors: YB
authors: Park
authors: Hyo-Soo
authors: HS
authors: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050814:Octamer Transcription Factor-3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse