Editor's Note: Acute liver failure (ALF) is a severe liver injury caused by factors such as drugs, viruses, and ischemia-reperfusion injury, leading to massive hepatocyte apoptosis, necrosis, and potentially irreversible liver damage. The condition progresses rapidly, with high short-term mortality rates and poor prognosis, while medical treatment options are limited. Although liver transplantation is an effective strategy for treating ALF, its high cost, scarcity of donor livers, and lifelong requirement for immunosuppressants limit its clinical application. Therefore, new treatment methods for ALF are urgently needed. On June 7, 2024, at the European Association for the Study of the Liver (EASL) annual meeting in Milan, a study by Professor Yu Chen's team from Beijing YouAn Hospital, Capital Medical University, was presented as a poster (Abstract No. FRI-347). This study revealed the mechanism by which liver-derived stem cells (HYX1) can be used to treat ALF, providing new insights for the future clinical treatment of ALF.Stem cell transplantation for liver disease has received extensive attention in recent years. Stem cells are non-terminally differentiated cells with self-renewal and replication capabilities, capable of differentiating into various tissue types and cells, thus promoting liver regeneration. Currently, liver stem cells are the most studied in cell therapy. Professor Yu Chen’s team successfully constructed a human adult liver-derived stem cell line HYX1 using related technologies. Compared to other liver stem cells, HYX1 cells originate from the liver environment, have low immunogenicity, high proliferation and differentiation potential, and significant advantages in genomic stability and immune rejection, making them ideal cells for liver cell replacement therapy. However, post-transplant cell survival rates are low, cells are difficult to expand in vitro, they easily lose liver characteristics, and there is a risk of malignant transformation, thus limiting the application of stem cells.
Previous studies have shown that exosomes derived from stem cells can act as signal transduction mediators, regulating the biological functions of target cells. In previous research, Professor Yu Chen’s team demonstrated that transplantation of HYX1 stem cells can exert liver protective effects against ALF. At this year’s EASL annual meeting, their reported study aimed to further demonstrate the liver protective effects of HYX1-derived exosomes on an animal model of ALF induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) and to analyze the potential molecular mechanisms.
Researchers pre-treated normal mice with HYX1-Exos or PBS, then induced ALF using D-GalN/LPS. Results showed that compared to the PBS pre-treatment group, HYX1-Exos significantly alleviated ALF in mice, evidenced by improved liver structure and lower pathology scores.
Next, the researchers performed miRNA sequencing and KEGG enrichment analysis on HYX1-Exos. miRNA sequencing analysis showed that miRNAs from HYX1-Exos were enriched in the ferroptosis signaling pathway, which plays a key role in ALF.
The researchers further screened and identified the specific miRNA let-7c-5p related to ferroptosis. They injected let-7c-5p agomir or a negative control into normal mice, then induced ALF with D-GalN/LPS. Results showed that let-7c-5p agomir significantly reduced liver injury and inhibited ferroptosis. Dual-luciferase assays indicated a targeting relationship between let-7c-5p and SLC11A2. Compared to control cells, cells overexpressing SLC11A2 showed decreased viability and increased ferroptosis levels. Notably, the liver protective effects conferred by HYX1-Exos or let-7c-5p agomir were significantly weakened in cells overexpressing SLC11A2 compared to control cells.
In summary, this study indicates that HYX1-Exos carrying let-7c-5p can alleviate ALF by inhibiting SLC11A2-mediated ferroptosis. This finding provides new insights into the pathogenesis and treatment of ALF.
Original Source: Huixin Tang, Li Bai, Yu Chen. “HYX1-derived Exosomal let-7c-5p Protects Against Acute Liver Failure by Inhibiting SLC11A2-mediated Ferroptosis.” EASL 2024 Abstract FRI-347
