The alterations in the extracellular matrix composition guide the repair of damaged liver tissue.
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.
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
Mariliis
M
Klaas
Laboratory of Physics of Nano Structures, Institute of Physics, University of Tartu, Estonia.
Triin
T
Kangur
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
Janeli
J
Viil
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
Kristina
K
Mäemets-Allas
Department of Pathological Anatomy and Forensic Medicine, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia.|Department of Pathology, Clinic of Diagnostics, West Tallinn Central Hospital, Estonia.
Ave
A
Minajeva
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.
Krista
K
Vadi
Laboratory of Physics of Nano Structures, Institute of Physics, University of Tartu, Estonia.
Mikk
M
Antsov
Department of Pathology, Clinic of Diagnostics, West Tallinn Central Hospital, Estonia.
Natalia
N
Lapidus
Laboratory of Physics of Nano Structures, Institute of Physics, University of Tartu, Estonia.
Martin
M
Järvekülg
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Estonia.|Department of Biosciences, Karolinska Institutet, Stockholm, Sweden.
Viljar
V
Jaks
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence