title: Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human Mesenchymal Stem Cells: Involvement of HIF-1α, FASN, and mTORC1.
abstract: The control of stem cells by oxygen signaling is an important way to improve various stem cell physiological functions and metabolic nutrient alteration. Lipid metabolism alteration via hypoxia is thought to be a key factor in controlling stem cell fate and function. However, the interaction between hypoxia and the metabolic and functional changes to stem cells is incompletely described. This study aimed to identify hypoxia-inducible lipid metabolic enzymes that can regulate umbilical cord blood (UCB)-derived human mesenchymal stem cell (hMSC) proliferation and migration and to demonstrate the signaling pathway that controls functional change in UCB-hMSCs. Our results indicate that hypoxia treatment stimulates UCB-hMSC proliferation, and expression of two lipogenic enzymes: fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1). FASN but not SCD1 is a key enzyme for regulation of UCB-hMSC proliferation and migration. Hypoxia-induced FASN expression was controlled by the hypoxia-inducible factor-1 alpha (HIF-1α)/SCAP/SREBP1 pathway. Mammalian target of rapamycin (mTOR) was phosphorylated by hypoxia, whereas inhibition of FASN by cerulenin suppressed hypoxia-induced mTOR phosphorylation as well as UCB-hMSC proliferation and migration. RAPTOR small interfering RNA transfection significantly inhibited hypoxia-induced proliferation and migration. Hypoxia-induced mTOR also regulated CDK2, CDK4, cyclin D1, cyclin E, and F-actin expression as well as that of c-myc, p-cofilin, profilin, and Rho GTPase. Taken together, the results suggest that mTORC1 mainly regulates UCB-hMSC proliferation and migration under hypoxia conditions via control of cell cycle and F-actin organization modulating factors. In conclusion, the HIF-1α/FASN/mTORC1 axis is a key pathway linking hypoxia-induced lipid metabolism with proliferation and migration in UCB-hMSCs. Stem Cells 2015;33:2182-2195.
authors.affiliation: BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.
authors.forename: Hyun Jik
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.affiliation: BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Jung
authors.affiliation: BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.
authors.forename: Sang Yub
authors.initials: SY
authors.lastname: Oh
authors.affiliation: BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.|Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D002454:Cell Differentiation; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Cell migration; Cell proliferation; Fatty acid synthase; Hypoxia; Hypoxia-inducible factor 1; Mammalian target of rapamycin