title: Fibronectin Extra Domain A Promotes Liver Sinusoid Repair following Hepatectomy.
abstract: 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.
authors.affiliation: Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Cell and Molecular Biology Graduate Group, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Bridget
authors.initials: B
authors.lastname: Sackey-Aboagye
authors.affiliation: Cell and Molecular Biology Graduate Group, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Olsen
authors.affiliation: Department of Physiology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sarmistha M
authors.initials: SM
authors.lastname: Mukherjee
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Sciences, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ventriglia
authors.affiliation: Hiroshima University, Hiroshima, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Yokosaki
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Greenbaum
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Sciences, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gi Yun
authors.initials: GY
authors.lastname: Lee
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hani
authors.initials: H
authors.lastname: Naga
authors.affiliation: Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.|Cell and Molecular Biology Graduate Group, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rebecca G
authors.identifier: http://orcid.org/0000-0002-6988-4102
authors.initials: RG
authors.lastname: Wells
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002196:Capillaries / Q000166:cytology; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006498:Hepatectomy; D016023:Integrins / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000502:physiology* / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D000072417:Protein Domains; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014945:Wound Healing / Q000235:genetics*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D005353:Fibronectins; D016023:Integrins; D020033:Protein Isoforms; D000099152:Cadherin 5; C113256:integrin alpha 9 beta 1