Fibronectin EIIIA splice variant promotes liver sinusoid repair following hepatectomy

Liver sinusoidal endothelial cells (LSECs) are the main endothelial cells in the liver and are important for maintaining liver homeostasis as well as responding to injury. LSECs express cellular fibronectin containing the alternatively spliced extra domain A (EIIIA) and increase expression of this isoform in response to liver injury, although its function is not well understood. Here, I examined the role of EIIIA in sinusoid repair and liver regeneration by carrying out partial hepatectomies in mice lacking EIIIA or their wild type littermates. In vitro, I studied LSEC adhesion on decellularized, EIIIA-containing matrices and investigated the role of cellular fibronectins in LSEC tubulogenesis. I found that liver regeneration was significantly delayed and that sinusoidal repair was impaired in EIIIA-/- mice, especially females, as was the lipid accumulation typical of the post-hepatectomy liver. In vitro, I observed that primary LSECs were more adhesive to cell-deposited matrices containing EIIIA and that cellular fibronectin enhanced LSEC tubulogenesis and vascular cord formation. The integrin α9β1 , which specifically binds EIIIA, promoted adhesion of LSECs to EIIIA and tubulogenesis. My graduate project’s findings identify a role for EIIIA in liver regeneration. The study suggests that sinusoidal repair and the ability to deliver lipids mobilized from peripheral stores as an energy source for regeneration is enhanced by increased LSEC adhesion, which is mediated by EIIIA