PMID- 27956229
OWN - NLM
STAT- MEDLINE
DCOM- 20170613
LR  - 20220409
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 152
IP  - 5
DP  - 2017 Apr
TI  - Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects 
      Against Liver Fibrosis in Mice.
PG  - 1174-1186
LID - S0016-5085(16)35463-4 [pii]
LID - 10.1053/j.gastro.2016.12.003 [doi]
AB  - BACKGROUND & AIMS: Mesenchymal stem cells (MSCs) mediate tissue repair and might 
      be used to prevent or reduce liver fibrosis. However, little is known about the 
      anti-fibrotic factors secreted from MSCs or their mechanisms. METHODS: Umbilical 
      cord-derived MSCs (UCMSCs) were differentiated into hepatocyte-like cells 
      (hpUCMSCs), medium was collected, and secretome proteins were identified and 
      quantified using nanochip-liquid chromatography/quadrupole time-of-flight mass 
      spectrometry. Liver fibrosis was induced in mice by intraperitoneal injection of 
      thioacetamide or CCl(4); some mice were then given injections of secretomes or 
      proteins. Liver tissues were collected and analyzed by histology or polymerase 
      chain reaction array to analyze changes in gene expression patterns. We analyzed 
      the effects of MSC secretomes and potential anti-fibrotic proteins on 
      transforming growth factor beta 1 (TGFbeta1)-mediated activation of human hepatic 
      stellate cell (HSC) lines (hTert-HSC and LX2) and human primary HSCs. Liver 
      tissues were collected from 16 patients with liver cirrhosis and 16 individuals 
      without cirrhosis (controls) in Korea and analyzed by immunohistochemistry and 
      immunoblots. RESULTS: In mice with fibrosis, accumulation of extracellular matrix 
      proteins was significantly reduced 3 days after injecting secretomes from UCMSCs, 
      and to a greater extent from hpUCMSCs; numbers of activated HSCs that expressed 
      the myogenic marker alpha-smooth muscle actin (alpha-SMA, encoded by ACTA2 [actin, alpha 
      2, smooth muscle]) were also reduced. Secretomes from UCMSCs, and to a greater 
      extent from hpUCMSCs, reduced liver expression of multiple fibrotic factors, 
      collagens, metalloproteinases, TGFbeta, and Smad proteins in the TGFbeta signaling 
      pathways. In HSC cell lines and primary HSCs, TGFbeta1-stimulated upregulation of 
      alpha-SMA was significantly inhibited (and SMAD2 phosphorylation reduced) by 
      secretomes from UCMSCs, and to a greater extent from hpUCMSCs. We identified 32 
      proteins in secretomes of UCMSCs that were more highly concentrated in secretomes 
      from hpUCMSCs and inhibited TGFbeta-mediated activation of HSCs. One of these, milk 
      fat globule-EGF factor 8 (MFGE8), was a strong inhibitor of activation of human 
      primary HSCs. We found MFGE8 to down-regulate expression of TGFbeta type I receptor 
      by binding to alpha(v)beta(3) integrin on HSCs and to be secreted by MSCs from umbilical 
      cord, teeth, and bone marrow. In mice, injection of recombinant human MFGE8 had 
      anti-fibrotic effects comparable to those of the hpUCMSC secretome, reducing 
      extracellular matrix deposition and HSC activation. Co-injection of an antibody 
      against MFGE8 reduced the anti-fibrotic effects of the hpUCMSC secretome in mice. 
      Levels of MFGE8 were reduced in cirrhotic liver tissue from patients compared 
      with controls. CONCLUSIONS: MFGE8 is an anti-fibrotic protein in MSC secretomes 
      that strongly inhibits TGFbeta signaling and reduces extracellular matrix deposition 
      and liver fibrosis in mice.
CI  - Copyright (c) 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - An, Su Yeon
AU  - An SY
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Jang, Yu Jin
AU  - Jang YJ
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Lim, Hee-Joung
AU  - Lim HJ
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Han, Jiyou
AU  - Han J
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Lee, Jaehun
AU  - Lee J
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Lee, Gyunggyu
AU  - Lee G
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Park, Ji Young
AU  - Park JY
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Park, Seo-Young
AU  - Park SY
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea.
FAU - Kim, Ji Hyang
AU  - Kim JH
AD  - Biotechnology Research Institute, HurimBioCell Inc., Seoul, Republic of Korea.
FAU - Do, Byung-Rok
AU  - Do BR
AD  - Biotechnology Research Institute, HurimBioCell Inc., Seoul, Republic of Korea.
FAU - Han, Choongseong
AU  - Han C
AD  - Department of Oral Medicine and Oral Diagnosis, Seoul National University Dental 
      Hospital, School of Dentistry and Dental Research Institute, Seoul National 
      University, Seoul, Republic of Korea; Nexel, Co., Ltd, Seoul, Republic of Korea.
FAU - Park, Hee-Kyung
AU  - Park HK
AD  - Department of Oral Medicine and Oral Diagnosis, Seoul National University Dental 
      Hospital, School of Dentistry and Dental Research Institute, Seoul National 
      University, Seoul, Republic of Korea.
FAU - Kim, Ok-Hee
AU  - Kim OH
AD  - Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Daejeon, Republic of Korea.
FAU - Song, Myeong Jun
AU  - Song MJ
AD  - Division of Hepatology, Department of Internal Medicine, Daejeon St. Mary's 
      Hospital, College of Medicine, The Catholic University of Korea, Daejeon, 
      Republic of Korea.
FAU - Kim, Say-June
AU  - Kim SJ
AD  - Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Daejeon, Republic of Korea.
FAU - Kim, Jong-Hoon
AU  - Kim JH
AD  - Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, 
      College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea. Electronic address: jhkim@korea.ac.kr.
LA  - eng
PT  - Journal Article
DEP - 20161209
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Antigens, Surface)
RN  - 0 (Integrin alphaVbeta3)
RN  - 0 (MFGE8 protein, human)
RN  - 0 (Mfge8 protein, mouse)
RN  - 0 (Milk Proteins)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Smad2 Protein)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Tgfb1 protein, mouse)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 075T165X8M (Thioacetamide)
RN  - 9007-34-5 (Collagen)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - EC 3.4.- (Metalloproteases)
SB  - IM
CIN - Gastroenterology. 2017 Apr;152(5):943-946. PMID: 28259796
CIN - Gastroenterology. 2017 Apr;152(5):1244. PMID: 28273437
MH  - Animals
MH  - Antigens, Surface/*metabolism
MH  - Carbon Tetrachloride/toxicity
MH  - Cell Line
MH  - Collagen/metabolism
MH  - Extracellular Matrix/metabolism
MH  - Hepatic Stellate Cells
MH  - Hepatocytes
MH  - Humans
MH  - Integrin alphaVbeta3/metabolism
MH  - Liver Cirrhosis/chemically induced/*metabolism/pathology
MH  - Male
MH  - Mesenchymal Stem Cells/metabolism
MH  - Metabolome
MH  - Metalloproteases/metabolism
MH  - Mice
MH  - Milk Proteins/*metabolism
MH  - Receptors, Transforming Growth Factor beta/metabolism
MH  - Smad2 Protein/metabolism
MH  - Thioacetamide/toxicity
MH  - Transforming Growth Factor beta1/metabolism
OTO - NOTNLM
OT  - Decorin
OT  - MMP
OT  - Mouse Model
OT  - Signal Transduction
EDAT- 2016/12/14 06:00
MHDA- 2017/06/14 06:00
CRDT- 2016/12/14 06:00
PHST- 2016/03/14 00:00 [received]
PHST- 2016/11/16 00:00 [revised]
PHST- 2016/12/03 00:00 [accepted]
PHST- 2016/12/14 06:00 [pubmed]
PHST- 2017/06/14 06:00 [medline]
PHST- 2016/12/14 06:00 [entrez]
AID - S0016-5085(16)35463-4 [pii]
AID - 10.1053/j.gastro.2016.12.003 [doi]
PST - ppublish
SO  - Gastroenterology. 2017 Apr;152(5):1174-1186. doi: 10.1053/j.gastro.2016.12.003. 
      Epub 2016 Dec 9.