Intimate cross-talk between HSC and LSEC contributes to activation and deactivation of hepatic sinusoidal cells

Background and Aims: Sinusoidal cells cross-talk has been proposed as an important mode of communication between liver cells in cirrhosis. Indeed, liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC)... [ view full abstract ]

Background and Aims: Sinusoidal cells cross-talk has been proposed as an important mode of communication between liver cells in cirrhosis. Indeed, liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) communicate each other in response to pharmacological treatments; however the effect of cross-talk between cirrhotic and control hepatic sinusoidal on cell activation and deactivation is unknown. We have herein analyzed this cross-talk in in vitro models. Methods: HSC and LSEC were isolated from CCl₄-cirrhotic and control rats, cultured alone or in a cross-talk model for 24h. The cross-talk between cirrhotic cells on controls (activation) and healthy cells on cirrhotic (deactivation) was analyzed. Cellular phenotypes were analyzed by qPCR (HSC: αSMA, col1α1 and TGFβ; LSEC: CD31, iNOS, endothelin-1 and kdr). Results: Cirrhotic-LSEC favored the activation of control-HSC (+57% in αSMA and +311% in col1α1), which was not observed when co-cultured with control-LSEC. On the other hand, control-HSC, but not cirrhotic-HSC, prevented control-LSEC activation (-62% in CD31, -82% in iNOS and -62% in endothelin-1). These results suggest that cirrhotic sinusoidal cells do not maintain control cell phenotype but favors cell activation. Nevertheless, significant de-activation of cirrhotic-HSC (-50% in αSMA and -18% in TGFβ) was observed when co-cultured with control-LSEC, but not with cirrhotic-LSEC. Interestingly, no changes in cirrhotic-LSEC were observed when co-cultured with control-HSC. Altogether suggesting a major role for LSEC in HSC deactivation. Conclusions: HSC and LSEC communication contributes to both the activation and deactivation of hepatic sinusoidal cells, and therefore represents a potential therapeutic way to improve liver disease.