Nuclear deformation mediates liver cell mechanosensing in cirrhosis
Sergi Guixé‐Muntet, Martí Ortega‐Ribera, Cong Wang, Sonia Selicean, Ion Andreu, Zanetta Kechagia, Constantino Fondevila, Pere Roca‐Cusachs, Jean‐François Dufour, Jaime Bosch, Annalisa Berzigotti, Jordi Gracia‐Sancho
Abstract
BACKGROUND & AIMS: may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms. METHODS: Hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells were isolated from healthy rats or rats with cirrhosis (carbon tetrachloride or thioacetamide), and cultured on polyacrylamide gels with different physiologically relevant stiffness for 72 h. RESULTS: rigid matrix (assessed by quantitative morphology, mRNA expression, protein synthesis, and electron microscopy imaging). Additionally, stiffness modified the antifibrotic effects of liraglutide in stellate cells of rats with cirrhosis. Finally, evaluation of nuclear morphology revealed that high stiffness induced nuclei deformation in all cell types, an observation confirmed in cells from human livers. Disconnecting the nucleus from the cytoskeleton by cytoskeleton disruption or a defective form of nesprin 1 significantly recovered spherical nuclear shape and quiescent phenotype of cells. CONCLUSIONS: modulates the phenotype of healthy rats and liver cells of rats with cirrhosis by altering the nuclear morphology through cytoskeleton-derived mechanical forces. The reversibility of this mechanism suggests that targeting the stiffness-mediated intracellular mechanical tensions may represent a novel therapeutic strategy for ACLD. LAY SUMMARY: liver cells into believing they are in a healthy, soft liver improved their function and could potentially contribute to treat cirrhosis.