title: Semaphorin 3E secreted by damaged hepatocytes regulates the sinusoidal regeneration and liver fibrosis during liver regeneration.
abstract: The liver has a remarkable capacity to regenerate after injury. Although the regulatory mechanisms of hepatocytic regeneration have been a subject of intense study, the dynamism of the sinusoids, specialized blood vessels in the liver, remains largely unknown. Transient activation of hepatic stellate cells and hepatic sinusoidal endothelial cells, which constitute the sinusoids, contributes to liver regeneration during acute injury, whereas their sustained activation causes liver fibrosis during chronic injury. We focused on understanding the association between damaged hepatocytes and sinusoidal regeneration or liver fibrogenesis using a carbon tetrachloride-induced liver injury mouse model. Damaged hepatocytes rapidly expressed semaphorin 3E (Sema3e), which induced contraction of sinusoidal endothelial cells and thereby contributed to activating hepatic stellate cells for wound healing. In addition, ectopic and consecutive expression of Sema3e in hepatocytes by the hydrodynamic tail-vein injection method resulted in disorganized regeneration of sinusoids and sustained activation of hepatic stellate cells. In contrast, liver fibrosis ameliorated in Sema3e-knockout mice compared with wild-type mice in a chronic liver injury model. Our results indicate that Sema3e, secreted by damaged hepatocytes, affects sinusoidal regeneration in a paracrine manner during liver regeneration, suggesting that Sema3e is a novel therapeutic target in liver fibrogenesis.
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yagai
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyajima
authors.affiliation: Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address: tanaka@iam.u-tokyo.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000378:metabolism*
chemical_list: D039961:Semaphorins