Impaired integrin α5β1-mediated hepatocyte growth factor release by stellate cells of the aged liver

Laminin proteins are critically involved in HSC function which is further illustrated in this article. Here, the authors illustrate the mechanistic link between fluid mechanical forces, loss of important extracellular matrix proteins, such as laminins, and hepatic aging, and how it all leads to an impaired liver regeneration potential. The authors provide evidence that integrin α5β1 is an important mechanosensor in hepatic stellate cells (HSC) involved in shear stress-induced release of hepatocyte growth factor (HGF), an essential inductor of liver regeneration which is impaired during aging. The expression of the integrin subunits α5 and β1 decreases in liver and HSC from aged rats. CRISPR/Cas9-mediated integrin α5 and β1 knockouts in isolated HSC lead to lowered HGF release and impaired cellular adhesion. Fluid mechanical forces increase integrin α5 and laminin gene expression whereas integrin β1 remains unaffected. In the aged liver, laminin β2 and γ1 protein chains as components of laminin-521 are lowered. The integrin α5 knockout in HSC reduces laminin expression via mechanosensory mechanisms. Culture of HSC on nanostructured surfaces functionalized with laminin-521 enhances HGF expression in HSC, demonstrating that these laminin proteins are critically involved in HSC function. During aging, HSC acquires a senescence-associated secretory phenotype and lower their growth factor expression essential for tissue repair. These findings suggest that impaired mechanosensing via integrin α5β1 in HSC contributes to the age-related reduction of ECM and HGF release that could affect liver regeneration.