IMT504 ameliorates liver fibrosis in mice

BORDA M; CANTERO MJ; FIORE EJ; GIARDELLI G; ALVARADO F; DÍAZ PEDRAZA M; MONTANER A; MAZZOLINI G; AQUINO JB

Mar del Plata

Congreso; Annual Meeting SAIC, SAB, AAF, AACYTAL; 2023

SAIC, SAB, AAF, AACYTAL

Objectives: To evaluate the effect of IMT504 during fibrogenesis or on a fibrotic liver in mice. Materials and methods: Liver fibrosis was established by applications of thioacetamide (TAA) or by bile duct ligation, and IMT504 was i.p. injected. A direct role of IMT504 and/or conditioned media (CM) of bone marrow stromal progenitors (BMSPs) subpopulations, pre-treated or not with IMT504, on relevant cellular types was analyzed. Histochemical, immunostaining, and qPCR assays were applied. Results: IMT504 inhibited liver fibrogenesis in both in vivo models, and accelerated the regression of a fibrotic liver in the TAA model, almost to normal. In mice treated with TAA for 2 or 8 weeks, and 1 day after the application of IMT504, it was found that the application of this ODN and the CM of GLAST+ Wnt1+ BMSPs pre-incubated with IMT504 reduced the mRNA expression levels of profibrogenic and pro-inflammatory factors, and increased the levels of anti-inflammatory markers, in samples of whole liver. Within the fraction enriched in parenchymal cells, markers involved in proliferation, hepatocyte functionality, and DNA repair and quality control of DNA synthesis were found to be overexpressed, while Gadd45α (a marker of cellular stress, DNA damage and cell cycle arrest) was down-regulated. Furthermore, these treatments: directly converted fibrotic macrophages towards a tolerogenic and pro-regenerative (upregulation of HGF) phenotype; significantly deactivated hepatic stellate cells and induced overexpression of HGF and IGF-I in primary cultured hepatocytes. Conclusions: IMT504 has a potent antifibrotic effect through different parallel mechanisms, and at the same time it also induces liver regeneration.