Overexpression of bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans

Novo E, Marra F, Zamara E, Valfre di Bonzo L, Monitillo L, Cannito S, Petrai I, Mazzocca A, Bonacchi A, Defranco R, Colombatto S, Autelli R, Pinzani M and Parola M
Source: Gut
Publication Date: (2006)
Issue: 55(8): 1174-82
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Myofibroblast, human hepatic
Species: human
Tissue Origin: liver
Nucleofector® I/II/2b
Background/Aims. Myofibroblast - like cells originating from the activation of hepatic stellate cells (HSC/MFs) play a key role in liver fibrosis, a potentially reversible process that may rely on induction of HSC/MFs apoptosis. While this possibility has been shown in cultured rat HSC, very limited data are currently available for human HSC/MFs. Methods. Cultured human HSC/MFs were exposed to several pro-apoptotic stimuli, including those known to induce apoptosis in rat HSC/MFs, and induction of cell death and related mechanisms were investigated using morphology, molecular biology and biochemical techniques. Results. In this study we report that fully activated human HSC/MFs did not undergo spontaneous apoptosis and survived to prolonged serum deprivation, Fas activation, or exposure to NGF, TNFa, oxidative stress mediators, doxorubicin and etoposide. Induction of caspase-dependent, mitochondria - driven apoptosis in HSC/MFs was observed only when protein synthesis or transcription were inhibited. Importantly, the process of HSC activation was accompanied by changes in the expression of a set of genes involved in apoptosis control. In particular, activated human HSC/MFs in culture overexpressed Bcl-2. The role of Bcl-2 was crucial since Bcl-2 silenced cells became susceptible to TNFa - induced apoptosis. Finally, Bcl-2 is markedly expressed in HSC/MFs present in liver tissue obtained from patients with HCV-related cirrhosis. Conclusions. Human activated HSC/MFs are resistant to most pro-apoptotic stimuli due to Bcl-2 overexpression and this feature may play a key role in the progression of fibrosis in chronic liver diseases.