New insights in cellular crosstalk of hepatic stellate cells and the effect of tissue stiffness in liver fibrosis
New insights in cellular crosstalk of hepatic stellate cells and the effect of tissue stiffness in liver fibrosis
Liver fibrosis is a pathological response to chronic liver injury, characterized by excessive extracellular matrix (ECM) deposition and hepatic stellate cell (HSC) activation, which can progress to cirrhosis and liver failure without effective intervention. Targeting HSCs and the liver microenvironment is considered a promising anti-fibrotic strategy.
This thesis of Qiqi Zhou investigated a new insights in cellular crosstalk of hepatic stellate cells and the effect of tissue stiffness in liver fibrosis. MSCs inhibited HSC activation in vitro and reversed CClâ‚„-induced fibrosis in vivo. This anti-fibrotic capability is mainly due to soluble factors secreted by MSCs. Contrary to extracellular vesicles from other cell types, MSCs do not induce senescence of activated HSCs. In our study, during the onset and progression of liver fibrosis, mechanical stiffness of the liver increases remarkably. We demonstrated that 3D liver-ECM hydrogels had a stiffness of ~1 kPa and caused a decrease in HSC activation compared to 2D cultured HSCs in plastic tissue culture plates. Low-stiffness (~1 kPa) liver-ECM hydrogels attenuated HSC activation and maintained quiescence, whereas stiffer matrices (10~100 kPa) reduced this effect. Liver-ECM hydrogel could supports the culture, growth, formation and differentiation of human liver organoids. Furthermore, liver-ECM-grown organoids deposit collagen I around the organoid, which provides new opportunities to study the role of liver epithelial cells in ECM remodeling.
These findings advance understanding of the interactions among HSCs, ECM mechanics, and liver fibrosis. MSC therapy and mechanical modulation targeting represent promising anti-fibrotic strategies and may guide the development of more effective therapies for chronic liver disease.