1. Human umbilical cord-derived mesenchymal stem cells ameliorate liver fibrosis by improving mitochondrial function via Slc25a47-Sirt3 signaling pathway.
- Author
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Chen P, Yuan M, Yao L, Xiong Z, Liu P, Wang Z, Jiang Y, and Li L
- Subjects
- Animals, Humans, Mice, Hydrogen Peroxide pharmacology, Mitochondria metabolism, NAD metabolism, Signal Transduction, Umbilical Cord metabolism, Liver Cirrhosis metabolism, Liver Cirrhosis therapy, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism, Mitochondrial Diseases metabolism, Sirtuin 3 metabolism, Mitochondrial Membrane Transport Proteins metabolism
- Abstract
Chronic Liver fibrosis may progress to liver cirrhosis and hepatocellular carcinoma (HCC), hence cause a substantial global burden. However, effective therapies for blocking fibrosis are still lacking. Although mesenchymal stem cells (MSCs) have been proven beneficial to liver regeneration after damage, the underlying mechanism of their therapeutic effects are not fully understood. Oxidative stress and mitochondrial functionality alteration directly contributes to the hepatocyte apoptosis and development of liver fibrosis. This study aims to elucidate the mechanism by which hUC-MSC alleviates liver fibrosis and mitochondrial dysfunction. RNA-sequencing was performed to characterize the transcriptomic changes after implantation of hUC-MSCs in mice with liver fibrosis. Next, western blot, RT-PCR, immunohistochemical and immunofluorescence staining were used to evaluate the expression of different genes in vitro and in vivo. Additionally, mitochondrial morphological and dynamic changes, ROS content, and ATP production were examined. Slc25a47, a newly identified liver-specific mitochondrial NAD
+ transporter, was notably reduced in CCl4 -treated mice and H2 O2 -stimulated hepatocytes. Conversely, hUC-MSCs increased the Slc25a47 expression and NAD+ level within mitochondria, thereby enhanced Sirt3 protein activity and alleviated mitochondrial dysfunction in the liver. Furthermore, Slc25a47 knockdown could partially abrogate the protective effects of hUC-MSCs on H2 O2 -induced mitochondrial fission and oxidative stress in hepatocytes. Our study illustrates that Slc25a47 is a key molecular for hUC-MSCs to improve liver fibrosis and regulates mitochondrial function through Sirt3 for the first time, and providing a theoretical basis for the clinical translation of hUC-MSCs transplantation in the treatment of patients with liver fibrosis/cirrhosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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