Mesenchymal Stem Cell-Derived Exosomes Mitigate Acute Murine Liver Injury via Ets-1 and Heme Oxygenase-1 Up-regulation


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Abstract

Background:Mesenchymal stem cells (MSCs)-derived exosomes have been previously demonstrated to promote tissue regeneration in various animal disease models. This study investigated the protective effect of exosome treatment in carbon tetrachloride (CCl4)-induced acute liver injury and delineated possible underlying mechanism

Methods:Exosomes collected from conditioned media of previously characterized human umbilical cord-derived MSCs were intravenously administered into male CD-1 mice with CCl4-induced acute liver injury. Biochemical, histological and molecular parameters were used to evaluate the severity of liver injury. A rat hepatocyte cell line, Clone-9, was used to validate the molecular changes by exosome treatment.

Results:Exosome treatment significantly suppressed plasma levels of AST, ALT, and pro-inflammatory cytokines, including IL-6 and TNF-α, in the mice with CCl4-induced acute liver injury. Histological morphometry revealed a significant reduction in the necropoptic area in the injured livers following exosome therapy. Consistently, western blot analysis indicated marked elevations in hepatic expression of PCNA, c-Met, Ets-1, and HO-1 proteins after exosome treatment. Besides, the phosphorylation level of signaling mediator JNK was significantly increased, and that of p38 was restored by exosome therapy. Immunohistochemistry double staining confirmed nuclear Ets-1 expression and cytoplasmic localization of c-Met and HO-1 proteins. In vitro studies demonstrated that exosome treatment increased the proliferation of Clone-9 hepatocytes and protected them from CCl4-induced cytotoxicity. Kinase inhibition experiment indicated that the exosome-driven hepatoprotection might be mediated through the JNK pathway.

Conclusion:Exosome therapy activates the JNK signaling activation pathway as well as up-regulates Ets-1 and HO-1 expression, thereby protecting hepatocytes against hepatotoxin-induced cell death.

About the authors

Ying-Hsien Kao

Department of Medical Research, E-Da Hospital, I-Shou University

Author for correspondence.
Email: info@benthamscience.net

Chih-Yang Chang

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University

Email: info@benthamscience.net

Yu-Chun Lin

Department of Surgery, E-Da Hospital, I-Shou University

Email: info@benthamscience.net

Po-Han Chen

Department of Medical Research, E-Da Hospital, I-Shou University

Email: info@benthamscience.net

Po-Huang Lee

Department of Surgery, E-Da Hospital, I-Shou University

Email: info@benthamscience.net

Huoy-Rou Chang

Departments of Biomedical Engineering, I-Shou University

Email: info@benthamscience.net

Wen-Yu Chang

Department of Dermatology, E-- Da Cancer Hospital, I-Shou University

Email: info@benthamscience.net

Yo-Chen Chang

Department of Ophthalmology, Kaohsiung Medical University

Email: info@benthamscience.net

Shen-Fa Wun

Departments of Biomedical Engineering, I-Shou University

Email: info@benthamscience.net

Cheuk-Kwan Sun

Department of Medical Research, E-Da Hospital, I-Shou University

Author for correspondence.
Email: info@benthamscience.net

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