Work

Mesenchymal stem cell–derived exosome delivery of let-7a-5p enhances macrophage efferocytosis via Arid3a/Mertk axis in acute-on-chronic liver failure

Year: 2025

Type: article

Abstract: BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear. METHODS: The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential. RESULTS: Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes. CONCLUSION: MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy.

Source: Stem Cells Translational Medicine

DOI: 10.1093/stcltm/szaf058