PMID- 31847135
OWN - NLM
STAT- MEDLINE
DCOM- 20200428
LR  - 20200428
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 20
IP  - 24
DP  - 2019 Dec 13
TI  - A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from 
      Etanercept-Synthesizing Adipose-Derived Stem Cells.
LID - 10.3390/ijms20246302 [doi]
LID - 6302
AB  - Tumor necrosis factor-alpha (TNF-alpha)-driven inflammatory reaction plays a crucial role 
      in the initiation of liver fibrosis. We herein attempted to design genetically 
      engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-alpha 
      inhibitor), and to determine the anti-fibrotic potential of the secretome 
      released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we 
      generated the etanercept-synthesizing ASCs by transfecting the ASCs with 
      mini-circle plasmids containing the gene insert encoding for etanercept. We 
      subsequently collected the secretory material released from the 
      etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in 
      vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in 
      TAA-treated mice) models of liver fibrosis. We observed that while 
      etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes 
      (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs 
      (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration 
      of the etanercept-secretome induced significant reduction in the expression of 
      both fibrosis-related and inflammation-related markers compared to the control 
      group (all Ps < 0.05). The etanercept-secretome group also showed significantly 
      lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such 
      as TNF-alpha (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver 
      showed the highest reduction in the degree of fibrosis in the 
      entanercept-secretome group (p = 0.006). Our results suggest that the 
      administration of etanercept-secretome improves liver fibrosis by inhibiting 
      TNF-alpha-driven inflammation in the mice with liver fibrosis. Thus, blocking 
      TNF-alpha-driven inflammation at the appropriate stage of liver fibrosis could be an 
      efficient strategy to prevent fibrosis.
FAU - Han, Jae Hyun
AU  - Han JH
AUID- ORCID: 0000-0001-8012-1168
AD  - Department of Surgery, St. Vincent Hospital, College of Medicine, The Catholic 
      University of Korea, Seoul 16247, Korea.
FAU - Kim, Ok-Hee
AU  - Kim OH
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
FAU - Lee, Sang Chul
AU  - Lee SC
AD  - Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 34943, Korea.
FAU - Kim, Kee-Hwan
AU  - Kim KH
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
AD  - Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 11765, Korea.
FAU - Park, Jung Hyun
AU  - Park JH
AUID- ORCID: 0000-0003-2693-0655
AD  - Department of Surgery, Eunpeong St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 03312, Korea.
FAU - Lee, Jae Im
AU  - Lee JI
AD  - Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 11765, Korea.
FAU - Lee, Kyung Hee
AU  - Lee KH
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
FAU - Hong, Ha-Eun
AU  - Hong HE
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
FAU - Seo, Haeyeon
AU  - Seo H
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
FAU - Choi, Ho Joong
AU  - Choi HJ
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
FAU - Ju, Ji Hyeon
AU  - Ju JH
AD  - Division of Rheumatology, Department of internal medicine, Seoul St. Mary's 
      Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, 
      Korea.
FAU - Kim, Say-June
AU  - Kim SJ
AD  - Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The 
      Catholic University of Korea, Seoul 06591, Korea.
AD  - Catholic Central Laboratory of Surgery, College of Medicine, The Catholic 
      University of Korea, Seoul 06591, Korea.
LA  - eng
GR  - NRF-2018R1D1A1B07043081/National Research Foundation of Korea/
GR  - 2017/Seoul St. Mary's Hospital, The Catholic University of Korea/
PT  - Journal Article
DEP - 20191213
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 075T165X8M (Thioacetamide)
RN  - OP401G7OJC (Etanercept)
SB  - IM
MH  - Adipose Tissue/*metabolism/pathology
MH  - Cell Line
MH  - Etanercept/*metabolism
MH  - Humans
MH  - Interleukin-6/genetics/metabolism
MH  - Liver Cirrhosis/chemically induced/genetics/metabolism/*prevention & control
MH  - Stem Cells/*metabolism/pathology
MH  - Thioacetamide/adverse effects/pharmacology
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
PMC - PMC6940971
OTO - NOTNLM
OT  - adipose-derived stem cells
OT  - etanercept
OT  - liver fibrosis
OT  - secretome
OT  - tumor necrosis factor-alpha (TNF-alpha)
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2019/12/19 06:00
MHDA- 2020/04/29 06:00
PMCR- 2019/12/01
CRDT- 2019/12/19 06:00
PHST- 2019/11/06 00:00 [received]
PHST- 2019/12/11 00:00 [revised]
PHST- 2019/12/11 00:00 [accepted]
PHST- 2019/12/19 06:00 [entrez]
PHST- 2019/12/19 06:00 [pubmed]
PHST- 2020/04/29 06:00 [medline]
PHST- 2019/12/01 00:00 [pmc-release]
AID - ijms20246302 [pii]
AID - ijms-20-06302 [pii]
AID - 10.3390/ijms20246302 [doi]
PST - epublish
SO  - Int J Mol Sci. 2019 Dec 13;20(24):6302. doi: 10.3390/ijms20246302.