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

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 XIH (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 EVE-mediated fibrin-fibronectin provisional matrix is a critical step for ECM remodeling, we show in an FXIII subunit A deficient murine model of acute fiver injury that the lack of FXIII subunit A did not interfere with collagen reconstruction and resolution after liver injury. Furthermore, FXIII 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 crosslinked matrix could promote survival signals for hepatocytes in adult tissue remodeling. (Am,J Pathol. 2011, 179:3011-3019; DOI: 10.1016/j.ajpath.2011.08.037)