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Liver fibrosis, acute liver injury or liver failure, liver tumors, and immune rejection after liver transplantation are common clinical liver diseases. Immune responses are the key to determining the prognosis of liver diseases. Liver transplantation could be the last resort for patients with liver failure. However, the use of liver transplantation is limited because of the scarcity of organ donors, immunological rejection in recipients, and high cost. Mesenchymal stem cells (MSCs) are pluripotent adult stem cells with extensive anti‐inflammatory and immunomodulation effects. MSCs can be effectively used for treating liver diseases but without the limitations that are associated with liver transplantation. Therefore, several clinical trials have utilized MSCs for the treatment of refractory liver diseases and the related mechanism is increasingly being elucidated. We have mainly summarized the recent studies that focus on the immunomodulation mechanism of MSC therapy in liver diseases. Further, we have presented our insights on the prospects of using MSCs in the treatment of liver diseases. [ABSTRACT FROM AUTHOR]

Chronic liver disease inevitably progresses to liver cirrhosis, significantly compromising patients' overall survival and quality of life. However, a glimmer of hope emerges with the emergence of mesenchymal stem cells, possessing remarkable abilities for self-renewal, differentiation, and immunomodulation. Leveraging their potential, MSCs have become a focal point in both basic and clinical trials, offering a promising therapeutic avenue to impede fibrosis progression and enhance the life expectancy of individuals battling hepatic cirrhosis. This comprehensive review serves to shed light on the origin of MSCs, the intricate mechanisms underlying cirrhosis treatment, and the cutting-edge advancements in basic and clinical research surrounding MSC-based therapies for liver cirrhosis patients. • Liver cirrhosis is the final stage of many chronic liver diseases. • Mesenchymal stem cells (MSCs) have paracrine, anti-fibrotic, anti-oxidative stress, and immunomodulatory effects, making them a potential treatment option for liver cirrhosis. • MSC-EVs, gene modification, hypoxia, preconditioning with cytokines or growth factors, and combination therapy can enhance the therapeutic effect of MSCs in treating liver cirrhosis. • Clinical trials have proven MSCs' safety and effectiveness in treating liver cirrhosis. [ABSTRACT FROM AUTHOR]

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 CCl 4 -treated mice and H 2 O 2 -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 H 2 O 2 -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. • hUC-MSCs transplantation alleviate mice liver fibrosis and improve liver function. • mitochondrial NAD+ transporter Slc25a47 was decreased under stressful conditions. • hUC-MSCs reduced hepatic oxidative stress and mitochondrial damage. • hUC-MSCs improve mitochondrial dysfunction via increasing Slc25a47 expression and protein activity of Sirt3. [ABSTRACT FROM AUTHOR]

• hUC-MSCs significantly improved liver function and alleviated liver fibrosis in mice induced by CCl4. • hUC-MSCs inhibit fibrosis by up-regulating the expression of miR-148a-5p in LX2 cells through exosomes pathway. • hUC-MSCs inhibit HSC activation by regulating the miR-148a-5p/SLIT3 axis. • SLIT3 is a promising biomarker for monitoring the advancement of liver fibrosis. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have garnered considerable attention as prospective modalities of treatment for liver fibrosis (LF). The inhibition of hepatic stellate cell (HSC) activation underlies the anti-fibrotic effects of hUC-MSCs. However, the precise mechanism by which hUC-MSCs impede HSC activation remains unclarified. We aimed to elucidate the intrinsic mechanisms underlying the therapeutic effects of hUC-MSCs in LF patients. Mice with liver cirrhosis induced by carbon tetrachloride (CCl 4) were used as experimental models and administered hUC-MSCs via tail-vein injection. The alterations in inflammation and fibrosis were evaluated through histopathological examinations. RNA sequencing (RNA-seq) and bioinformatics analysis were then conducted to investigate the therapeutic mechanism of hUC-MSCs. Finally, an in-vitro experiment involving the co-cultivation of hUC-MSCs or hUC-MSC-derived exosomes (MSC-Exos) with LX2 cells was performed to validate the potential mechanism underlying the hepatoprotective effects of hUC-MSCs in LF patients. hUC-MSC therapy significantly improved liver function and alleviated LF in CCl 4 -induced mice. High-throughput RNA-Seq analysis identified 1142 differentially expressed genes that were potentially involved in mediating the therapeutic effects of hUC-MSCs. These genes play an important role in regulating the extracellular matrix. miRNA expression data (GSE151098) indicated that the miR-148a-5p level was downregulated in LF samples, but restored following hUC-MSC treatment. miR-148a-5p was delivered to LX2 cells by hUC-MSCs via the exosome pathway, and the upregulated expression of miR-148a-5p significantly suppressed the expression of the activated phenotype of LX2 cells. SLIT3 was identified within the pool of potential target genes regulated by miR-148a-5p. Furthermore, hUC-MSC administration upregulated the expression of miR-148a-5p, which played a crucial role in suppressing the expression of SLIT3, thereby palliating fibrosis. hUC-MSCs inhibit the activation of HSCs through the miR-148a-5p/SLIT3 pathway and are thus capable of alleviating LF. [ABSTRACT FROM AUTHOR]

[Display omitted] • hUC-MSCs improved liver function and attenuated liver fibrosis in mice. • hUC-MSCs inhibit HSC activation by regulating the Hippo/YAP/Id1 axis. • hUC-MSCs secrete CCL2 to promote an anti-inflammatory macrophage phenotype. Few effective anti-fibrotic therapies are currently available for liver cirrhosis. Mesenchymal stromal cells (MSCs) ameliorate liver fibrosis and contribute to liver regeneration after cirrhosis, attracting much attention as a potential therapeutic strategy for the disease. However, the underlying molecular mechanism of their therapeutic effect is still unclear. Here, we investigated the effect of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in treating liver cirrhosis and their underlying mechanisms. We used carbon tetrachloride (CCl 4)-induced mice as liver cirrhosis models and treated them with hUC-MSCs via tail vein injection. We assessed the changes in liver function, inflammation, and fibrosis by histopathology and serum biochemistry and explored the mechanism of hUC-MSCs by RNA sequencing (RNA-seq) using liver tissues. In addition, we investigated the effects of hUC-MSCs on hepatic stellate cells (HSC) and macrophages by in vitro co-culture experiments. We found that hUC-MSCs considerably improved liver function and attenuated liver inflammation and fibrosis in CCl 4 -injured mice. We also showed that these cells exerted therapeutic effects by regulating the Hippo/YAP/Id1 axis in vivo. Our in vitro experiments demonstrated that hUC-MSCs inhibit HSC activation by regulating the Hippo/YAP signaling pathway and targeting Id1. Moreover, hUC-MSCs also alleviated liver inflammation by promoting the transformation of macrophages to an anti-inflammatory phenotype. Our study reveals that hUC-MSCs relieve liver cirrhosis in mice through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanisms, providing a theoretical basis for the future use of these cells as a potential therapeutic strategy for patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]