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Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models

INTRODUCTION: Mesenchymal stem cell-conditioned medium (MSC-CM) has been shown to have protective effects against various cellular-injury models. This mechanism of protection, however, has yet to be elucidated. Recently, exosomes were identified as the active component in MSC-CM. The aim of this stu...

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Autores principales: Tan, Cheau Yih, Lai, Ruenn Chai, Wong, Winnie, Dan, Yock Young, Lim, Sai-Kiang, Ho, Han Kiat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229780/
https://www.ncbi.nlm.nih.gov/pubmed/24915963
http://dx.doi.org/10.1186/scrt465
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author Tan, Cheau Yih
Lai, Ruenn Chai
Wong, Winnie
Dan, Yock Young
Lim, Sai-Kiang
Ho, Han Kiat
author_facet Tan, Cheau Yih
Lai, Ruenn Chai
Wong, Winnie
Dan, Yock Young
Lim, Sai-Kiang
Ho, Han Kiat
author_sort Tan, Cheau Yih
collection PubMed
description INTRODUCTION: Mesenchymal stem cell-conditioned medium (MSC-CM) has been shown to have protective effects against various cellular-injury models. This mechanism of protection, however, has yet to be elucidated. Recently, exosomes were identified as the active component in MSC-CM. The aim of this study is to investigate the effect of MSC-derived exosomes in an established carbon tetrachloride (CCl(4))-induced liver injury mouse model. This potential effect is then validated by using in vitro xenobiotic-induced liver-injury assays: (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H(2)O(2))-induced liver injury. METHODS: The exosomes were introduced concurrent with CCl(4) into a mouse model through different routes of administration. Biochemical analysis was performed based on the blood and liver tissues. Subsequently the exosomes were treated in APAP and H(2)O(2)-toxicants with in vitro models. Cell viability was measured, and biomarkers indicative of regenerative and oxidative biochemical responses were determined to probe the mechanism of any hepatoprotective activity observed. RESULTS: In contrast to mice treated with phosphate-buffered saline, CCl(4) injury in mice was attenuated by concurrent-treatment exosomes, and characterized by an increase in hepatocyte proliferation, as demonstrated with proliferating cell nuclear antigen (PCNA) elevation. Significantly higher cell viability was demonstrated in the exosomes-treated group compared with the non-exosome-treated group in both injury models. The higher survival rate was associated with upregulation of the priming-phase genes during liver regeneration, which subsequently led to higher expression of proliferation proteins (PCNA and cyclin D1) in the exosomes-treated group. Exosomes also inhibited the APAP- and H(2)O(2)-induced hepatocytes apoptosis through upregulation of Bcl-(xL) protein expression. However, exosomes do not mitigate hepatocyte injury via modulation of oxidative stress. CONCLUSIONS: In summary, these results suggest that MSC-derived exosomes can elicit hepatoprotective effects against toxicants-induced injury, mainly through activation of proliferative and regenerative responses.
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spelling pubmed-42297802014-11-14 Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models Tan, Cheau Yih Lai, Ruenn Chai Wong, Winnie Dan, Yock Young Lim, Sai-Kiang Ho, Han Kiat Stem Cell Res Ther Research INTRODUCTION: Mesenchymal stem cell-conditioned medium (MSC-CM) has been shown to have protective effects against various cellular-injury models. This mechanism of protection, however, has yet to be elucidated. Recently, exosomes were identified as the active component in MSC-CM. The aim of this study is to investigate the effect of MSC-derived exosomes in an established carbon tetrachloride (CCl(4))-induced liver injury mouse model. This potential effect is then validated by using in vitro xenobiotic-induced liver-injury assays: (1) acetaminophen (APAP)- and (2) hydrogen peroxide (H(2)O(2))-induced liver injury. METHODS: The exosomes were introduced concurrent with CCl(4) into a mouse model through different routes of administration. Biochemical analysis was performed based on the blood and liver tissues. Subsequently the exosomes were treated in APAP and H(2)O(2)-toxicants with in vitro models. Cell viability was measured, and biomarkers indicative of regenerative and oxidative biochemical responses were determined to probe the mechanism of any hepatoprotective activity observed. RESULTS: In contrast to mice treated with phosphate-buffered saline, CCl(4) injury in mice was attenuated by concurrent-treatment exosomes, and characterized by an increase in hepatocyte proliferation, as demonstrated with proliferating cell nuclear antigen (PCNA) elevation. Significantly higher cell viability was demonstrated in the exosomes-treated group compared with the non-exosome-treated group in both injury models. The higher survival rate was associated with upregulation of the priming-phase genes during liver regeneration, which subsequently led to higher expression of proliferation proteins (PCNA and cyclin D1) in the exosomes-treated group. Exosomes also inhibited the APAP- and H(2)O(2)-induced hepatocytes apoptosis through upregulation of Bcl-(xL) protein expression. However, exosomes do not mitigate hepatocyte injury via modulation of oxidative stress. CONCLUSIONS: In summary, these results suggest that MSC-derived exosomes can elicit hepatoprotective effects against toxicants-induced injury, mainly through activation of proliferative and regenerative responses. BioMed Central 2014-06-10 /pmc/articles/PMC4229780/ /pubmed/24915963 http://dx.doi.org/10.1186/scrt465 Text en Copyright © 2014 Tan et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Tan, Cheau Yih
Lai, Ruenn Chai
Wong, Winnie
Dan, Yock Young
Lim, Sai-Kiang
Ho, Han Kiat
Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title_full Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title_fullStr Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title_full_unstemmed Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title_short Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
title_sort mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229780/
https://www.ncbi.nlm.nih.gov/pubmed/24915963
http://dx.doi.org/10.1186/scrt465
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