Abstract
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.
Highlights
Liver injury of any kind induces several molecular changes that eventually lead to the progressive fibrosis of the parenchyma and development of liver cirrhosis, the end stage of chronic liver disease.Changes at the liver endothelium level are crucial in the pathogenesis of liver fibrosis and represent the main focus of this review.The liver has a unique vascular supply where two main venous vascular systems and the hepatic artery interact
Some evidences suggest that shear stress acting on Liver sinusoidal endothelial cells (LSEC) following resection could be a key factor in regulating liver regeneration [196,197], the real contribution of shear stress to LSEC dysfunction and its potential therapeutic targeting remain to be elucidated
Liver regeneration involves a synchronized cooperation between parenchymal and non-parenchymal cells [198,199,200,201,202,203] where LSEC orchestrate the secretion of cytokines and growth factors necessaries for hepatocyte proliferation
Summary
Liver injury of any kind induces several molecular changes that eventually lead to the progressive fibrosis of the parenchyma and development of liver cirrhosis, the end stage of chronic liver disease. LSEC are first defense barrier and contribute to hemostasis/thrombosis, metabolite transport, inflammation, angiogenesis, and vascular tone regulation They participate in the liver cellular response to a given injury by regulating the neighboring cells [1,5,6], mainly hepatic stellate cells (HSC), the principal source of extracellular matrix (ECM) and the key player in fibrosis progression [7]. If the damaging stimulus exceeds the regenerative capacity of the liver and the injury persists, the response becomes excessive Perpetuation of this “curative” response translates to fibrosis progression, substituting hepatic tissue by a fibrous scar disrupting vascular architecture and liver parenchyma [8,10].
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