SPARC down-regulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF.

ATORRASAGASTI, CATALINA; AQUINO JB; HOFMAN L; ALANIZ L; MALVICINI M; MARIANA GARCIA; BENEDETTI L; FRIEDMAN SL; PODHAJCER OL; MAZZOLINI GD

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

AMER PHYSIOLOGICAL SOC

Año: 2011 p. 739 - 748

0193-1857

Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted Protein, Acidic and Rich in Cysteine (SPARC) is an ECM protein with many biological functions, that is over-expressed in cirrhotic livers and up-regulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC down-regulation ameliorates liver fibrosis in vivo. In order to uncover the cellular mechanisms involved, we have specifically knocked-down SPARC in two aHSC lines: the CFSC-2G (rat) and the LX-2 (human) and in primary cultured rat aHSCs. Transient down-regulation of SPARC in HSCs did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knock-down increased HSC adhesion to fibronectin and significantly decreased their migration towards PDFG-BB and TGF-. Interestingly, TGF-1 secretion by HSCs was reduced following SPARC siRNA-treatment and pre-incubation with TGF-1 restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF1-mediated induction of SPARC expression; thus, SPARC knock-down seems to exert its effects on HSCs partially through modulation of TGF-1 expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e. down-regulation of N-cadherin and up-regulation of E-cadherin. Our data together suggest that the up-regulation of SPARC previously reported for aHSCs partially mediates pro-fibrogenic activities of TGF- and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.