Abstract
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.
Highlights
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs resolving chronic liver diseases
Injection of High mobility group box 1 (HMGB1) peptide attenuated liver damage and promoted the regression of fibrosis in model mice with Carbon tetrachloride (CCl4)-induced liver damage To evaluate the therapeutic effects of HMGB1 peptide, HMGB1 peptide was injected into mice twice a week for 4 weeks using CCl4-induced cirrhosis model mice (Fig. 1A), and serum biochemical tests and fibrosis accumulation were evaluated compared with the normal saline (NS) injection control group
These results revealed that injection of HMGB1 peptide effectively attenuated liver damage, increased ALB production, and alleviated fibrosis
Summary
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs resolving chronic liver diseases. Thomas et al reported that regression of fibrosis could be achieved by injecting bone marrowderived macrophages through the portal vein [4] Based on these results, Forbes et al performed a phase I study using an injection of autologous cultured macrophages for cirrhosis; the approach was shown to be safe, and researchers have moved to phase II studies of this treatment [5]. Forbes et al performed a phase I study using an injection of autologous cultured macrophages for cirrhosis; the approach was shown to be safe, and researchers have moved to phase II studies of this treatment [5] Another therapy that can induce these endogenous systems is that using mesenchymal stem cells (MSCs). Induction of anti-inflammatory or scar-resolving macrophages is fundamental for the treatment of cirrhosis, and substances or drugs inducing these macrophages may have applications in future cell-free therapies [1, 2]
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