Critical Role of Factor XIII in the Initial Stages of Carbon Tetrachloride–Induced Adult Liver Remodeling

• Published in: The American journal of pathology Vol. 179; no. 6; pp. 3011 - 3019
• Main Authors: Tsujimoto, Ikuko, Moriya, Kei, Sakai, Keiko, Dickneite, Gerhard, Sakai, Takao
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-12-2011; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis; Biological and medical sciences; Carbon Tetrachloride - toxicity; Cell Adhesion - physiology; Cell Proliferation; Cell Transdifferentiation - physiology; Chemical and Drug Induced Liver Injury - physiopathology; Collagen - physiology; Cross-Linking Reagents - metabolism; Extracellular Matrix - physiology; Factor XIII - physiology; Factor XIII Deficiency - physiopathology; Factor XIIIa - physiology; Fibrin - physiology; Fibrinogen - physiology; Fibroblasts - physiology; Fibronectins - physiology; Hepatic Stellate Cells - physiology; Investigative techniques, diagnostic techniques (general aspects); MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mice, Inbred CBA; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Wound Healing - physiology; Human; Anatomic pathology; Clinical stage; Digestive system; Factor XIII; Liver; Carbon tetrachloride; Adult; Remodeling
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2011.08.037

The transglutaminase-mediated, covalent cross-linking of proteins is an essential step in tissue remodeling after injury. This process provides tissues with extra rigidity and resistance against proteolytic degradation. Plasma coagulation factor XIII (FXIII) is a transglutaminase that promotes cross-linking of the extracellular matrix (ECM) components fibrin and fibronectin to form a provisional matrix in response to tissue damage. However, the functional requirement for this FXIII-mediated cross-linked provisional matrix in adult tissue remodeling remains to be defined. Although it has been proposed that the formation FXIII-mediated fibrin-fibronectin provisional matrix is a critical step for ECM remodeling, we show in an FXIII subunit A–deficient murine model of acute liver injury that the lack of FXIII subunit A did not interfere with collagen reconstruction and resolution after liver injury. Furthermore, FXIIIA deficiency caused significantly increased hepatocyte apoptosis and a delay in hepatocyte regeneration after injury, which were accompanied by a significantly high induction of p53 expression. These findings suggest novel functions of FXIII that the FXIII-mediated covalently cross-linked matrix could promote survival signals for hepatocytes in adult tissue remodeling.