Back to Search
Start Over
SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2011 May; Vol. 300 (5), pp. G739-48. Date of Electronic Publication: 2011 Feb 10. - Publication Year :
- 2011
-
Abstract
- 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 overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. 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 downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β(1). Interestingly, TGF-β(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β(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., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Cell Adhesion Molecules
Cell Movement drug effects
Cell Proliferation drug effects
Collagen Type I biosynthesis
Coloring Agents
Down-Regulation drug effects
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix metabolism
Extracellular Matrix physiology
Osteonectin genetics
Phalloidine
RNA, Small Interfering pharmacology
Rats
Reverse Transcriptase Polymerase Chain Reaction
Hepatic Stellate Cells pathology
Liver Cirrhosis pathology
Osteonectin physiology
Platelet-Derived Growth Factor pharmacology
Transforming Growth Factor beta1 pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1547
- Volume :
- 300
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 21311029
- Full Text :
- https://doi.org/10.1152/ajpgi.00316.2010