CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in non-alcoholic steatohepatitis mice

Abstract

Abstract Background/purpose of the study: In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on NASH, which has been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating NASH livers. Methods CD34+ cells were isolated from mice bone marrow and effectively expanded over 7 days. The mice were assigned to either a normal chow diet or a choline-deficient, L-amino acid-defined, high-fat diet, which was followed for 12 and 20 weeks to create a mild and severe fibrosis model, respectively. Results Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/IRF7/STAT1/CXCL10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the NASH liver. Conclusions These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in NASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.