Fibronectin Extra Domain A Promotes Liver Sinusoid Repair following Hepatectomy

• Published in: PloS one Vol. 11; no. 10; p. e0163737
• Main Authors: Sackey-Aboagye, Bridget, Olsen, Abby L, Mukherjee, Sarmistha M, Ventriglia, Alexander, Yokosaki, Yasuyuki, Greenbaum, Linda E, Lee, Gi Yun, Naga, Hani, Wells, Rebecca G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-10-2016; Public Library of Science (PLoS)
• Subjects: Adhesion; Alternative splicing; Angiogenesis; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Bioengineering; Biology and Life Sciences; Biotechnology; Cadherins - genetics; Cadherins - metabolism; Capillaries - cytology; Cell Adhesion; Cell adhesion & migration; Cells, Cultured; Cloning; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium; Engineering schools; Extracellular matrix; Female; Females; Fibronectin; Fibronectins; Fibronectins - chemistry; Fibronectins - genetics; Fibronectins - metabolism; Hepatectomy; Hepatocytes; Hepatology; Homeostasis; Immunoglobulins; Integrins; Integrins - chemistry; Integrins - metabolism; Kinases; Liver; Liver - blood supply; Liver - physiology; Liver - surgery; Liver Regeneration - genetics; Mars; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Morphogenesis; Motility; Protein Binding; Protein Domains; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Regeneration; Repair; Research and Analysis Methods; Rodents; Up-Regulation; Wound healing; Wound Healing - genetics; United States > US; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0163737

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-cFN) and increase expression of this isoform after liver injury, although its function is not well understood. Here, we examined the role of EIIIA-cFN in liver regeneration following partial hepatectomy. We carried out two-thirds partial hepatectomies in mice lacking EIIIA-cFN and in their wild type littermates, studied liver endothelial cell adhesion on decellularized, EIIIA-cFN-containing matrices and investigated the role of cellular fibronectins in liver endothelial cell tubulogenesis. We found that liver weight recovery following hepatectomy was significantly delayed and that sinusoidal repair was impaired in EIIIA-cFN null mice, especially females, as was the lipid accumulation typical of the post-hepatectomy liver. In vitro, we found that liver endothelial cells were more adhesive to cell-deposited matrices containing the EIIIA domain and that cellular fibronectin enhanced tubulogenesis and vascular cord formation. The integrin α9β1, which specifically binds EIIIA-cFN, promoted tubulogenesis and adhesion of liver endothelial cells to EIIIA-cFN. Our findings identify a role for EIIIA-cFN in liver regeneration and tubulogenesis. We suggest that sinusoidal repair is enhanced by increased LSEC adhesion, which is mediated by EIIIA-cFN.