Abstract
While the cellular mechanisms of liver regeneration have been thoroughly studied, the role of extracellular matrix (ECM) in liver regeneration is still poorly understood. We utilized a proteomics-based approach to identify the shifts in ECM composition after CCl4 or DDC treatment and studied their effect on the proliferation of liver cells by combining biophysical and cell culture methods. We identified notable alterations in the ECM structural components (eg collagens I, IV, V, fibronectin, elastin) as well as in non-structural proteins (eg olfactomedin-4, thrombospondin-4, armadillo repeat-containing x-linked protein 2 (Armcx2)). Comparable alterations in ECM composition were seen in damaged human livers. The increase in collagen content and decrease in elastic fibers resulted in rearrangement and increased stiffness of damaged liver ECM. Interestingly, the alterations in ECM components were nonhomogenous and differed between periportal and pericentral areas and thus our experiments demonstrated the differential ability of selected ECM components to regulate the proliferation of hepatocytes and biliary cells. We define for the first time the alterations in the ECM composition of livers recovering from damage and present functional evidence for a coordinated ECM remodelling that ensures an efficient restoration of liver tissue.
Highlights
Increase rapidly during tissue regeneration[10]
Scanning electron microscopy (SEM) analysis revealed the loss of elastic fibers and microfibrils in damaged livers and the resulting increase in liver extracellular matrix (ECM) stiffness was identified with atomic force microscopy (AFM)
The liver damage-induced cell proliferation is accompanied by significant changes in liver ECM composition
Summary
Increase rapidly during tissue regeneration[10]. Recent studies showed that the absence of fibronectin in liver leads to more extensive liver cirrhosis induced by liver damage and was accompanied by increased liver stiffness and disorganized collagen network[11]. The aim of the current work was to identify the changes in the liver ECM composition during liver regeneration and to study the potential mechanisms by which these regulate the proliferative properties of liver cells. To achieve this we utilized two well-established mouse models of toxic liver injury coupled with tissue decellularization and mass spectrometry. Since the analysis of the growth promoting properties of these proteins in vitro showed selective enhancement of the proliferative potential of either hepatocytes and or non-hepatocyte cells encompassing the biliary cell compartment we outlined a model where the identified changes in ECM composition ensure coordinated restoration of liver tissue
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