title: Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation.
abstract: OBJECTIVE
  We previously reported that platelets promote hepatocyte proliferation. In this study, we focused on the role of platelets in liver sinusoidal endothelial cells (LSECs) in addition to their role in hepatocyte in liver regeneration.
  
  
  METHODS
  Immortalized human LSECs (TMNK-1) were used. The LSECs were co-cultured with human platelets, and the proliferation of LSECs and the excretion of growth factors and interleukin-6 (IL-6) were subsequently measured. The main factor from platelets which induced the excretion of IL-6 from LSECs was determined using inhibitors of each component contained in the platelets. The need for direct contact between platelets and LSECs was investigated using cell culture inserts. The proliferation of human primary hepatocytes was measured after the addition of the supernatant of LSECs cultured with or without platelets.
  
  
  RESULTS
  The number of LSECs cocultured with platelets significantly increased. Excretion of IL-6 and vascular endothelial growth factor (VEGF) increased in LSECs with platelets. JTE-013, a specific antagonist for sphingosine 1-phosphate (S1P) 2 receptors, inhibited the excretion of IL-6 from LSECs after the addition of platelets. When the platelets and LSECs were separated by the cell culture insert, the excretion of IL-6 from LSECs was decreased. DNA synthesis was significantly increased in human primary hepatocytes cultured with the supernatant of LSECs with platelets.
  
  
  CONCLUSIONS
  Platelets promote LSEC proliferation and induce IL-6 and VEGF production. Direct contact between the platelets and LSECs and S1P, that are contained in platelets, were involved in the excretion of IL-6 from LSECs. IL-6 from LSECs induced proliferation of parenchymal hepatocytes.
authors.affiliation: Department of Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Soichiro
authors.initials: S
authors.lastname: Murata
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Reiji
authors.initials: R
authors.lastname: Nozaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ohshiro
authors.forename: Naoya
authors.initials: N
authors.lastname: Ikeda
authors.forename: Sugiru
authors.initials: S
authors.lastname: Pak
authors.forename: Andriy
authors.initials: A
authors.lastname: Myronovych
authors.forename: Katsuji
authors.initials: K
authors.lastname: Hisakura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oda
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sasaki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
mesh_terms: D001792:Blood Platelets / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000166:cytology; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A