Good Manufacturing Practice-Derived Human Liver Stem Cell Extracellular Vesicles Attenuate Liver Fibrosis In Vivo.

Abstract

Human liver stem cells (HLSCs) are a mesenchymal stromal cell (MSC)-like population isolated from adult liver biopsies. HLSCs share key characteristics with MSCs, including phenotype and differentiation capabilities. Previous studies have demonstrated that HLSCs promote regeneration in different experimental models of acute and chronic tissue injury and that HLSC-derived extracellular vesicles (HLSC-EVs) recapitulate the therapeutic effects of the cells of origin. This study aimed to determine whether HLSC-EVs, obtained and characterized under good manufacturing practice (GMP) conditions, can influence the progression of liver fibrosis in vivo. The EV production process was carried out under GMP conditions to generate batches of HLSC-EVs by tangential flow filtration. To assess their therapeutic potential, an in vivo model of hepatic fibrosis was established through administration of thioacetamide (TAA). In TAA-treated mice, EV administrations attenuated fibrosis progression. Molecular analyses showed a significant reduction in the expression levels of key pro-fibrotic genes. At the functional level, EV administration resulted in a significant reduction in plasma alanine aminotransferase levels and an increase in albumin levels, indicating improved liver function. These data indicate that HLSC-EVs, produced under GMP conditions, display antifibrotic effects in a chronic liver disease model, leading to improved liver function and histology.