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A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

Tumor necrosis factor-α (TNF-α)-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-α inhibitor), and to determine the anti-fibrotic potential...

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Autores principales: Han, Jae Hyun, Kim, Ok-Hee, Lee, Sang Chul, Kim, Kee-Hwan, Park, Jung Hyun, Lee, Jae Im, Lee, Kyung Hee, Hong, Ha-Eun, Seo, Haeyeon, Choi, Ho Joong, Ju, Ji Hyeon, Kim, Say-June
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940971/
https://www.ncbi.nlm.nih.gov/pubmed/31847135
http://dx.doi.org/10.3390/ijms20246302
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author Han, Jae Hyun
Kim, Ok-Hee
Lee, Sang Chul
Kim, Kee-Hwan
Park, Jung Hyun
Lee, Jae Im
Lee, Kyung Hee
Hong, Ha-Eun
Seo, Haeyeon
Choi, Ho Joong
Ju, Ji Hyeon
Kim, Say-June
author_facet Han, Jae Hyun
Kim, Ok-Hee
Lee, Sang Chul
Kim, Kee-Hwan
Park, Jung Hyun
Lee, Jae Im
Lee, Kyung Hee
Hong, Ha-Eun
Seo, Haeyeon
Choi, Ho Joong
Ju, Ji Hyeon
Kim, Say-June
author_sort Han, Jae Hyun
collection PubMed
description Tumor necrosis factor-α (TNF-α)-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-α 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-α (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-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.
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spelling pubmed-69409712020-01-09 A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells Han, Jae Hyun Kim, Ok-Hee Lee, Sang Chul Kim, Kee-Hwan Park, Jung Hyun Lee, Jae Im Lee, Kyung Hee Hong, Ha-Eun Seo, Haeyeon Choi, Ho Joong Ju, Ji Hyeon Kim, Say-June Int J Mol Sci Article Tumor necrosis factor-α (TNF-α)-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-α 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-α (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-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis. MDPI 2019-12-13 /pmc/articles/PMC6940971/ /pubmed/31847135 http://dx.doi.org/10.3390/ijms20246302 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Jae Hyun
Kim, Ok-Hee
Lee, Sang Chul
Kim, Kee-Hwan
Park, Jung Hyun
Lee, Jae Im
Lee, Kyung Hee
Hong, Ha-Eun
Seo, Haeyeon
Choi, Ho Joong
Ju, Ji Hyeon
Kim, Say-June
A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title_full A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title_fullStr A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title_full_unstemmed A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title_short A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells
title_sort novel hepatic anti-fibrotic strategy utilizing the secretome released from etanercept-synthesizing adipose-derived stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940971/
https://www.ncbi.nlm.nih.gov/pubmed/31847135
http://dx.doi.org/10.3390/ijms20246302
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