A new perspective on mesenchymal stem cell-based therapy for liver diseases: restoring mitochondrial function.

Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and immunoregulation. Mitochondria are crucial in maintaining hepatocyte integrity and function. Mitochondrial dysfunction, such as impaired synthesis of adenosine triphosphate (ATP), decreased activity of respiratory chain complexes, and altered mitochondrial dynamics, is observed in most liver diseases. Accumulating evidence has substantiated that the therapeutic potential of MSCs is mediated not only through their cell replacement and paracrine effects but also through their regulation of mitochondrial dysfunction in liver disease. Here, we comprehensively review the involvement of mitochondrial dysfunction in the development of liver disease and how MSCs can target mitochondrial dysfunction. We also discuss recent advances in a novel method that modifies MSCs to enhance their functions in liver disease. A full understanding of MSC restoration of mitochondrial function and the underlying mechanisms will provide innovative strategies for clinical applications. Video Abstract.

Decreased miR-17-92 cluster correlates with senescence features, disrupted oxidative homeostasis, and impaired therapeutic efficacy of mesenchymal stem cells.

Aging and replicative cellular senescence are associated with the reduced therapeutic potential of mesenchymal stem cells (MSCs) on a variety of diseases. This study aimed to determine the mechanism in MSC senescence and further explore a modification strategy to reverse senescence-associated cell dysfunction to improve the therapeutic efficacy of MSCs on acute liver failure (ALF). We found that the adipose tissue-derived MSCs from old mice (oAMSCs) exhibited senescence phenotypes and showed reduced therapeutic efficacy in lipopolysaccharide and D-galactosamine-induced ALF, as shown by the increased hepatic necrosis, liver histology activity index scores, serum liver function indicator levels, and inflammatory cytokine levels. The expression of miR-17-92 cluster members, especially miR-17 and miR-20a, was obviously decreased in oAMSCs and replicatively senescent AMSCs, and was consistent with the decreased oncogene c-Myc level during AMSC senescence and may mediate c-Myc stemness addiction. Further experiments revealed that c-Myc-regulated miR-17-92 expression contributed to increased p21 expression and redox system dysregulation during AMSC senescence. Furthermore, modification of AMSCs with the two key miRNAs in the miR-17-92 cluster mentioned above reversed the senescence features of oAMSCs and restored the therapeutic effect of senescent AMSCs on ALF. In conclusion, the cellular miR-17-92 cluster level is correlated with AMSC senescence and can be used both as an index for evaluating and as a modification target for improving the therapeutic potential of AMSCs.NEW & NOTEWORTHY We reported for the first time that c-Myc-regulated miR-17-92 contributed to increased p21 expression and redox system dysregulation during AMSC senescence and was associated with the reduced therapeutic effects of senescent AMSCs on ALF. Moreover, modifying the expression of the miR-17-92 cluster members, especially miR-17 and/or miR-20a, could reverse AMSC senescence. Thus, miR-17-92 cluster can be used both as an index for evaluating and as a modification strategy for improving the therapeutic potential of AMSCs.

Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.