Antifibrotic effect on liver of a novel truncated isoform of the human TGF-â type II receptor Fc-tag protein

ANABELA LA COLLA; TANIA MELINA RODRÍGUEZ; MARCELA S. BERTOLIO; SABRINA CAMISANO; JORGE VELASCO ZAMORA; DEWEY, RICARDO A.; ANDREA N CHISARI

Congreso; LXIII ReuniOn Cientifica Anual de la Sociedad Argentina de Investigación Clínica; 2018

Liver fibrosis is a hallmark feature of chronic liver diseases, which affects millions of patients worldwide, and leads to liver failure. Current protective options for these patients are limited. We have recently described the presence in human cells of a new splicing variant of TGF-â type II receptor (TGFBR2) lacking the transmembrane and intracellular domains, thus rendering a truncated protein of 80 amino acids known as soluble endogenous TGFBR2 (TGFBR2-SE). It is well established that transforming growth factor beta (TGF-â) promotes liver fibrosis. Thus, the development of agents with a significant potential to achieve a specific and long-lasting interference of TGF-â action in vivo, is of clinical relevance. The aim of this work was to study the effect of lentiviral-mediated overexpression of TGFBR2-SE fused in frame with the human IgG1 (Lv-TGFBR2-SE/Fc), in a carbon tetrachloride (CCl4)-induced liver fibrosis rat model. We compared three experimental groups: vehicle, CCl4 and CCl4 previously administrated with LvTGFBR2-SE/Fc intrahepatically. In this way, we observed partial recovery of body weight in rats treated with Lv-TGFBR2-SE/Fc + CCl4 compared to the CCl4 group. In addition, gross appearance of liver in the Lv-TGFBR2-SE/Fc + CCl4 group showed reversion of the irregular shape and shrinkage observed in the CCl4 group. Moreover, administration of Lv-TGFBR2-SE/Fc diminished CCl4-induced liver enzyme increase, indicative of liver injury recovery. Histological analysis of liver sections revealed that Lv-TGFBR2-SE/Fc significantly decreased the deposition of collagen fibers induced by CCl4 as well as practically restored liver architecture. Moreover, immunohistochemical and Western-blot studies showed that the administration of Lv-TGFBR2SE/Fc significantly diminished á-smooth muscle actin (á-SMA) expression, indicative of a reduced activation of hepatic stellate cells (HSC). These results suggest that lentiviral delivery of TGFBR2 exerts a protective effect against liver fibrosis induced by CCl4 in rats.