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Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway

Background:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to ex... Full description

Journal Title: Chinese Medical Journal 2016, Vol.129 (8), p.967-975
Main Author: Ma, Hu-Cheng
Other Authors: Wang, Xin , Wu, Min-Na , Zhao, Xin , Yuan, Xian-Wen , Shi, Xiao-Lei
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: China: Wolters Kluwer - Medknow Publications
ID: ISSN: 0366-6999
Link: https://www.ncbi.nlm.nih.gov/pubmed/27064043
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recordid: cdi_doaj_primary_oai_doaj_org_article_d62cc48aeb5d441dad84ccd2f18781be
title: Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway
format: Article
creator:
  • Ma, Hu-Cheng
  • Wang, Xin
  • Wu, Min-Na
  • Zhao, Xin
  • Yuan, Xian-Wen
  • Shi, Xiao-Lei
subjects:
  • Activator of Transcription 3 Signaling Pathway
  • Analysis
  • Angiogenesis
  • Animals
  • Apoptosis
  • Bone marrow
  • Care and treatment
  • Conditioned Medium
  • Conditioned Medium
  • Immunoregulation
  • Liver Disease
  • Signal Transducer and Activator of Transcription 3 Signaling Pathway
  • Stem Cell Transplantation
  • Cytokines
  • digestive
  • Genetic transcription
  • Health aspects
  • Histology
  • Hospitals
  • Immunoregulation
  • Inflammation
  • Interleukin-10 - physiology
  • Interleukins
  • Laboratory animals
  • Liver
  • Liver - pathology
  • Liver Disease
  • Liver failure
  • Liver Failure, Acute - pathology
  • Liver Failure, Acute - therapy
  • Male
  • Medical research
  • Medical schools
  • Medicine
  • Mesenchymal Stem Cell Transplantation
  • oral
  • Original
  • Original Article
  • Rats
  • Rats, Sprague-Dawley
  • Rodents
  • Signal Transducer
  • Signal Transducer and Activator of Transcription 3 Signaling Pathway
  • Signal Transduction - physiology
  • skin physiology
  • STAT3 Transcription Factor - physiology
  • Stem Cell Transplantation
  • Stem cells
  • Surgery
  • Survival analysis
  • Tumor necrosis factor-TNF
  • 信号转导
  • 信号通路
  • 治疗效果
  • 白细胞介素-10
  • 肝功能
  • 转录激活因子
  • 骨髓间充质干细胞
ispartof: Chinese Medical Journal, 2016, Vol.129 (8), p.967-975
description: Background:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF.Methods:MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis.Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray.MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF.Liver function,survival rate,histology,and inflammatory factors were determined.Exogenous recombinant rat interleukin (IL)-10,anti-rat IL-10 antibody,and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM.Statistical analysis was performed with SPSS version 19.0,and all data were analyzed by the independent-sample t-test.Results:There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group,as well as ALF+MSCs-CM group and ALF+DMEM group (all P 〈 0.05).Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs.1709.75±372.12 U/L and 964.72±414.59 vs.1709.75±372.12 U/L,respectively,all P 〈 0.05);meanwhile,serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs.4234.35±807.30 U/L and 2739.83±587.33 vs.4234.35±807.30 U/L,respectively,all P 〈 0.05).Furthermore,MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ),IL-1β,IL-6 levels and increased serum IL-10 level compared with DMEM (all P 〈 0.05).Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-l 0 was the most distinct.Blocking of IL-10 confirmed the therapeutic significance of this cytokine.Phosphorylated STAT3 was upregulated after IL-l 0 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10.Conclusions:The factors released by MSCs,especially IL-10,have the potential for therapeutic recovery of ALF,and the STAT3 signaling pathway may mediate the anti-inflammatory
language: eng
source:
identifier: ISSN: 0366-6999
fulltext: no_fulltext
issn:
  • 0366-6999
  • 2542-5641
url: Link


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titleInterleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway
creatorMa, Hu-Cheng ; Wang, Xin ; Wu, Min-Na ; Zhao, Xin ; Yuan, Xian-Wen ; Shi, Xiao-Lei
creatorcontribMa, Hu-Cheng ; Wang, Xin ; Wu, Min-Na ; Zhao, Xin ; Yuan, Xian-Wen ; Shi, Xiao-Lei
descriptionBackground:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF.Methods:MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis.Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray.MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF.Liver function,survival rate,histology,and inflammatory factors were determined.Exogenous recombinant rat interleukin (IL)-10,anti-rat IL-10 antibody,and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM.Statistical analysis was performed with SPSS version 19.0,and all data were analyzed by the independent-sample t-test.Results:There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group,as well as ALF+MSCs-CM group and ALF+DMEM group (all P 〈 0.05).Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs.1709.75±372.12 U/L and 964.72±414.59 vs.1709.75±372.12 U/L,respectively,all P 〈 0.05);meanwhile,serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs.4234.35±807.30 U/L and 2739.83±587.33 vs.4234.35±807.30 U/L,respectively,all P 〈 0.05).Furthermore,MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ),IL-1β,IL-6 levels and increased serum IL-10 level compared with DMEM (all P 〈 0.05).Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-l 0 was the most distinct.Blocking of IL-10 confirmed the therapeutic significance of this cytokine.Phosphorylated STAT3 was upregulated after IL-l 0 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10.Conclusions:The factors released by MSCs,especially IL-10,have the potential for therapeutic recovery of ALF,and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10.
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1EISSN: 2542-5641
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languageeng
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subjectActivator of Transcription 3 Signaling Pathway ; Analysis ; Angiogenesis ; Animals ; Apoptosis ; Bone marrow ; Care and treatment ; Conditioned Medium ; Conditioned Medium; Immunoregulation; Liver Disease; Signal Transducer and Activator of Transcription 3 Signaling Pathway; Stem Cell Transplantation ; Cytokines ; digestive ; Genetic transcription ; Health aspects ; Histology ; Hospitals ; Immunoregulation ; Inflammation ; Interleukin-10 - physiology ; Interleukins ; Laboratory animals ; Liver ; Liver - pathology ; Liver Disease ; Liver failure ; Liver Failure, Acute - pathology ; Liver Failure, Acute - therapy ; Male ; Medical research ; Medical schools ; Medicine ; Mesenchymal Stem Cell Transplantation ; oral ; Original ; Original Article ; Rats ; Rats, Sprague-Dawley ; Rodents ; Signal Transducer ; Signal Transducer and Activator of Transcription 3 Signaling Pathway ; Signal Transduction - physiology ; skin physiology ; STAT3 Transcription Factor - physiology ; Stem Cell Transplantation ; Stem cells ; Surgery ; Survival analysis ; Tumor necrosis factor-TNF ; 信号转导 ; 信号通路 ; 治疗效果 ; 白细胞介素-10 ; 肝功能 ; 转录激活因子 ; 骨髓间充质干细胞
ispartofChinese Medical Journal, 2016, Vol.129 (8), p.967-975
rights
0COPYRIGHT 2016 Medknow Publications and Media Pvt. Ltd.
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2Copyright © Wanfang Data Co. Ltd. All Rights Reserved.
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0Ma, Hu-Cheng
1Wang, Xin
2Wu, Min-Na
3Zhao, Xin
4Yuan, Xian-Wen
5Shi, Xiao-Lei
title
0Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway
1Chinese Medical Journal
addtitleChinese Medical Journal
descriptionBackground:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF.Methods:MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis.Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray.MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF.Liver function,survival rate,histology,and inflammatory factors were determined.Exogenous recombinant rat interleukin (IL)-10,anti-rat IL-10 antibody,and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM.Statistical analysis was performed with SPSS version 19.0,and all data were analyzed by the independent-sample t-test.Results:There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group,as well as ALF+MSCs-CM group and ALF+DMEM group (all P 〈 0.05).Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs.1709.75±372.12 U/L and 964.72±414.59 vs.1709.75±372.12 U/L,respectively,all P 〈 0.05);meanwhile,serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs.4234.35±807.30 U/L and 2739.83±587.33 vs.4234.35±807.30 U/L,respectively,all P 〈 0.05).Furthermore,MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ),IL-1β,IL-6 levels and increased serum IL-10 level compared with DMEM (all P 〈 0.05).Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-l 0 was the most distinct.Blocking of IL-10 confirmed the therapeutic significance of this cytokine.Phosphorylated STAT3 was upregulated after IL-l 0 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10.Conclusions:The factors released by MSCs,especially IL-10,have the potential for therapeutic recovery of ALF,and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10.
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0Activator of Transcription 3 Signaling Pathway
1Analysis
2Angiogenesis
3Animals
4Apoptosis
5Bone marrow
6Care and treatment
7Conditioned Medium
8Conditioned Medium; Immunoregulation; Liver Disease; Signal Transducer and Activator of Transcription 3 Signaling Pathway; Stem Cell Transplantation
9Cytokines
10digestive
11Genetic transcription
12Health aspects
13Histology
14Hospitals
15Immunoregulation
16Inflammation
17Interleukin-10 - physiology
18Interleukins
19Laboratory animals
20Liver
21Liver - pathology
22Liver Disease
23Liver failure
24Liver Failure, Acute - pathology
25Liver Failure, Acute - therapy
26Male
27Medical research
28Medical schools
29Medicine
30Mesenchymal Stem Cell Transplantation
31oral
32Original
33Original Article
34Rats
35Rats, Sprague-Dawley
36Rodents
37Signal Transducer
38Signal Transducer and Activator of Transcription 3 Signaling Pathway
39Signal Transduction - physiology
40skin physiology
41STAT3 Transcription Factor - physiology
42Stem Cell Transplantation
43Stem cells
44Surgery
45Survival analysis
46Tumor necrosis factor-TNF
47信号转导
48信号通路
49治疗效果
50白细胞介素-10
51肝功能
52转录激活因子
53骨髓间充质干细胞
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titleInterleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway
authorMa, Hu-Cheng ; Wang, Xin ; Wu, Min-Na ; Zhao, Xin ; Yuan, Xian-Wen ; Shi, Xiao-Lei
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0Activator of Transcription 3 Signaling Pathway
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2Angiogenesis
3Animals
4Apoptosis
5Bone marrow
6Care and treatment
7Conditioned Medium
8Conditioned Medium; Immunoregulation; Liver Disease; Signal Transducer and Activator of Transcription 3 Signaling Pathway; Stem Cell Transplantation
9Cytokines
10digestive
11Genetic transcription
12Health aspects
13Histology
14Hospitals
15Immunoregulation
16Inflammation
17Interleukin-10 - physiology
18Interleukins
19Laboratory animals
20Liver
21Liver - pathology
22Liver Disease
23Liver failure
24Liver Failure, Acute - pathology
25Liver Failure, Acute - therapy
26Male
27Medical research
28Medical schools
29Medicine
30Mesenchymal Stem Cell Transplantation
31oral
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36Rodents
37Signal Transducer
38Signal Transducer and Activator of Transcription 3 Signaling Pathway
39Signal Transduction - physiology
40skin physiology
41STAT3 Transcription Factor - physiology
42Stem Cell Transplantation
43Stem cells
44Surgery
45Survival analysis
46Tumor necrosis factor-TNF
47信号转导
48信号通路
49治疗效果
50白细胞介素-10
51肝功能
52转录激活因子
53骨髓间充质干细胞
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2Wu, Min-Na
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jtitleChinese Medical Journal
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0Background:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF.Methods:MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis.Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray.MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF.Liver function,survival rate,histology,and inflammatory factors were determined.Exogenous recombinant rat interleukin (IL)-10,anti-rat IL-10 antibody,and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM.Statistical analysis was performed with SPSS version 19.0,and all data were analyzed by the independent-sample t-test.Results:There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group,as well as ALF+MSCs-CM group and ALF+DMEM group (all P 〈 0.05).Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs.1709.75±372.12 U/L and 964.72±414.59 vs.1709.75±372.12 U/L,respectively,all P 〈 0.05);meanwhile,serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs.4234.35±807.30 U/L and 2739.83±587.33 vs.4234.35±807.30 U/L,respectively,all P 〈 0.05).Furthermore,MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ),IL-1β,IL-6 levels and increased serum IL-10 level compared with DMEM (all P 〈 0.05).Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-l 0 was the most distinct.Blocking of IL-10 confirmed the therapeutic significance of this cytokine.Phosphorylated STAT3 was upregulated after IL-l 0 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10.Conclusions:The factors released by MSCs,especially IL-10,have the potential for therapeutic recovery of ALF,and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10.
111-2154/R
2Conditioned Medium; Immunoregulatiom Liver Disease; Signal Transducer and Activator of Transcription 3 Signaling Pathway; Stein Cell Transplantation
abstractBackground:Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF).However,the mechanism remains controversial.Recently,modulation of inflammation by MSCs has been regarded as a crucial mechanism.The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF.Methods:MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis.Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray.MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF.Liver function,survival rate,histology,and inflammatory factors were determined.Exogenous recombinant rat interleukin (IL)-10,anti-rat IL-10 antibody,and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM.Statistical analysis was performed with SPSS version 19.0,and all data were analyzed by the independent-sample t-test.Results:There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group,as well as ALF+MSCs-CM group and ALF+DMEM group (all P 〈 0.05).Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs.1709.75±372.12 U/L and 964.72±414.59 vs.1709.75±372.12 U/L,respectively,all P 〈 0.05);meanwhile,serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs.4234.35±807.30 U/L and 2739.83±587.33 vs.4234.35±807.30 U/L,respectively,all P 〈 0.05).Furthermore,MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ),IL-1β,IL-6 levels and increased serum IL-10 level compared with DMEM (all P 〈 0.05).Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-l 0 was the most distinct.Blocking of IL-10 confirmed the therapeutic significance of this cytokine.Phosphorylated STAT3 was upregulated after IL-l 0 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10.Conclusions:The factors released by MSCs,especially IL-10,have the potential for therapeutic recovery of ALF,and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10.
copChina
pubWolters Kluwer - Medknow Publications
pmid27064043
doi10.4103/0366-6999.179794
oafree_for_read