PMID- 25576343
OWN - NLM
STAT- MEDLINE
DCOM- 20150720
LR  - 20181202
IS  - 1535-3699 (Electronic)
IS  - 1535-3702 (Print)
IS  - 1535-3699 (Linking)
VI  - 240
IP  - 4
DP  - 2015 Apr
TI  - Extracellular regulated protein kinases 1/2 phosphorylation is required for 
      hepatic differentiation of human umbilical cord-derived mesenchymal stem cells.
PG  - 534-45
LID - 10.1177/1535370214548996 [doi]
AB  - Mesenchymal stem cells (MSCs) have the capacity to restore liver function by 
      differentiating into hepatocyte like cells. However, the underlying mechanisms 
      are not well understood. Here, we have investigated the signals involved in the 
      hepatic differentiation of human umbilical cord-derived mesenchymal stem cells 
      (hUCMSCs). hUCMSCs were treated with mouse fetal liver-conditioned medium (FLCM) 
      to induce hepatic differentiation. Flow cytometry, reverse transcription PCR, 
      real-time PCR, immunocytochemistry, and polymerase chain reaction (PCR) array 
      were used to detect the expression of MSC- and hepotocyte-specific markers in 
      FLCM-treated hUCMSCs. Urea production and cytochrome P450 3A4 (CYP3A4) activity 
      were used as indicators to evaluate liver cell characteristics. 
      Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated 
      kinase (ERK) was analyzed in hUCMSCs by Western blotting. Following FLCM 
      treatment, expression of MSC-specific markers decreased, while 
      hepatocyte-specific gene expression was increased. Urea production, albumin 
      secretion, glycogen storage, and CYP3A4 activity were significantly enhanced in 
      FLCM-treated cells. In addition, ERK1/2 phosphorylation was increased in a 
      time-dependent manner through Raf/MEK/ERK pathway, and phosphorylation was 
      sustained at a high level during hepatic induction. Inhibition of ERK1/2 
      activation by U0126 (an ERK1/2 inhibitor) and pFLAG-CMV-ERK1(K71R) (negative 
      mutant of ERK1) reversed the expression of liver-specific genes in hUCMSCs and 
      affected hepatic function significantly. In summary, this work shows that ERK1/2 
      phosphorylation plays an important role in inducing hepatic differentiation of 
      hUCMSCs in FLCM.
CI  - (c) 2015 by the Society for Experimental Biology and Medicine.
FAU - Yan, Yongmin
AU  - Yan Y
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Zhu, Yuan
AU  - Zhu Y
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Sun, Feng
AU  - Sun F
AD  - Clinical Laboratory of Nantong Tumour Hospital, Nantong, Jiangsu 226000, P.R. 
      China.
FAU - Zhang, Bin
AU  - Zhang B
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Li, Limin
AU  - Li L
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Sun, Zixuan
AU  - Sun Z
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Li, Wei
AU  - Li W
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Qian, Hui
AU  - Qian H
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China 
      icls@ujs.edu.cn 1stmmm1st@163.com.
FAU - Zhu, Wei
AU  - Zhu W
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
FAU - Xu, Wenrong
AU  - Xu W
AD  - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of 
      Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China The 
      Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China 
      icls@ujs.edu.cn 1stmmm1st@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150108
PL  - Switzerland
TA  - Exp Biol Med (Maywood)
JT  - Experimental biology and medicine (Maywood, N.J.)
JID - 100973463
RN  - 0 (Culture Media, Conditioned)
RN  - 8W8T17847W (Urea)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 2.7.11.1 (raf Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/*physiology
MH  - Cells, Cultured
MH  - Culture Media, Conditioned/pharmacology
MH  - Cytochrome P-450 CYP3A/metabolism
MH  - Fetal Blood/*cytology
MH  - Hepatocytes/*cytology/drug effects/metabolism
MH  - Humans
MH  - Mesenchymal Stem Cells/*cytology
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/*metabolism
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Phosphorylation
MH  - Signal Transduction/*physiology
MH  - Time Factors
MH  - Urea/metabolism
MH  - raf Kinases/metabolism
PMC - PMC4935372
OTO - NOTNLM
OT  - ERK1/2
OT  - fetal liver-conditioned medium
OT  - hepatocytes
OT  - umbilical cord-derived mesenchymal stem cell
EDAT- 2015/01/13 06:00
MHDA- 2015/07/21 06:00
PMCR- 2015/10/01
CRDT- 2015/01/11 06:00
PHST- 2014/02/18 00:00 [received]
PHST- 2014/07/16 00:00 [accepted]
PHST- 2015/01/11 06:00 [entrez]
PHST- 2015/01/13 06:00 [pubmed]
PHST- 2015/07/21 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - 1535370214548996 [pii]
AID - 10.1177_1535370214548996 [pii]
AID - 10.1177/1535370214548996 [doi]
PST - ppublish
SO  - Exp Biol Med (Maywood). 2015 Apr;240(4):534-45. doi: 10.1177/1535370214548996. 
      Epub 2015 Jan 8.