PMID- 25825864
OWN - NLM
STAT- MEDLINE
DCOM- 20160413
LR  - 20211203
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Linking)
VI  - 33
IP  - 7
DP  - 2015 Jul
TI  - Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human 
      Mesenchymal Stem Cells: Involvement of HIF-1alpha, FASN, and mTORC1.
PG  - 2182-95
LID - 10.1002/stem.2020 [doi]
AB  - 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-1alpha)/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-1alpha/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.
CI  - (c) 2015 AlphaMed Press.
FAU - Lee, Hyun Jik
AU  - Lee HJ
AD  - BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 
      Korea.
FAU - Ryu, Jung Min
AU  - Ryu JM
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, Seoul National University, Seoul, Korea.
FAU - Jung, Young Hyun
AU  - Jung YH
AD  - BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 
      Korea.
FAU - Oh, Sang Yub
AU  - Oh SY
AD  - BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 
      Korea.
FAU - Lee, Sei-Jung
AU  - Lee SJ
AD  - BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 
      Korea.
FAU - Han, Ho Jae
AU  - Han HJ
AD  - BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 
      Korea.
AD  - Department of Veterinary Physiology, College of Veterinary Medicine, Research 
      Institute for Veterinary Science, Seoul National University, Seoul, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150511
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.3.1.85 (FASN protein, human)
RN  - EC 2.3.1.85 (Fatty Acid Synthase, Type I)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Differentiation
MH  - Cell Hypoxia
MH  - Cell Movement
MH  - Cell Proliferation
MH  - Fatty Acid Synthase, Type I/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Mesenchymal Stem Cells/cytology/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Cell migration
OT  - Cell proliferation
OT  - Fatty acid synthase
OT  - Hypoxia
OT  - Hypoxia-inducible factor 1
OT  - Mammalian target of rapamycin
EDAT- 2015/04/01 06:00
MHDA- 2016/04/14 06:00
CRDT- 2015/04/01 06:00
PHST- 2014/08/31 00:00 [received]
PHST- 2015/02/28 00:00 [accepted]
PHST- 2015/04/01 06:00 [entrez]
PHST- 2015/04/01 06:00 [pubmed]
PHST- 2016/04/14 06:00 [medline]
AID - 10.1002/stem.2020 [doi]
PST - ppublish
SO  - Stem Cells. 2015 Jul;33(7):2182-95. doi: 10.1002/stem.2020. Epub 2015 May 11.