The evolving role of liver sinusoidal endothelial cells in liver health and disease

Abstract

LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.

Angiocrine Signaling in Sinusoidal Health and Disease

“…This contrasts abundant expression of Wnt2, Wnt9b, Lhx6, and cKit in pericentral LSECs and central venous endothelial cells. 6,23,24 The field has integrated these findings into cell type specific zonation marker panels necrosis with acetaminophen overdose (APAP) 38 (further discussed below). In the APAP model, Hgf expression and hepatocyte proliferation did not show zonation.…”

“…38,45 This was confirmed with single cell 'omics, further demonstrating that Wnt agonist administration late in APAP toxicity can support rodent liver regeneration by Wnt2 and Wnt9b induction. 45 In the PHx model, regeneration is a wellorganized, LSEC-driven series of events that includes the inductive phase of hepatocyte proliferation, angiogenic phase, and terminal phase 5,6 During the inductive phase, hepatocyte proliferation is stimulated via LSEC-derived nitric oxide signaling (NO), which can be stimulated via multiple mechanisms including flow-induced sheer stress and LSEC-derived HGF. 6,56,57 Indeed, increased HGF secretion activates c/MET, Deptor, liver kinase B1 and subsequent adenosine monophosphate-activated protein kinase (AMPK) phosphorylation to increase NO release via phosphorylated endothelial nitric oxide synthase (eNOS).…”

“…45 In the PHx model, regeneration is a wellorganized, LSEC-driven series of events that includes the inductive phase of hepatocyte proliferation, angiogenic phase, and terminal phase 5,6 During the inductive phase, hepatocyte proliferation is stimulated via LSEC-derived nitric oxide signaling (NO), which can be stimulated via multiple mechanisms including flow-induced sheer stress and LSEC-derived HGF. 6,56,57 Indeed, increased HGF secretion activates c/MET, Deptor, liver kinase B1 and subsequent adenosine monophosphate-activated protein kinase (AMPK) phosphorylation to increase NO release via phosphorylated endothelial nitric oxide synthase (eNOS). 54,58 In addition, Wnt2 release for hepatocyte proliferation can be regulated downstream of the VEGFR-2/inhibitor of the DNA binding 1 (ID1) axis.…”

“…87 A subset of patients with NAFLD develop non-alcoholic steatohepatitis (NASH), which is characterized by the release of toxic lipids, increase of inflammation and development of liver fibrosis. 6 LSEC phenotype can be affected in the lipotoxic hepatic microenvironment during the development of NAFLD toward NASH (Figure 2). Although one study reports that LSEC fenestrae are preserved at 20 weeks of high fat diet, 88 several other studies confirm a loss of the fenestrae due to high-fat high-carbohydrate diet, choline-deficient high-fat diet, choline-deficient L-amino-acid-defined high-fat diet with 0.1% methionine, or 22-24 weeks of high-fat diet.…”

Editorial: Hepatic immune response underlying liver cirrhosis and portal hypertension

“…LSECs are the most abundant nonparenchymal cells in the liver and are the gatekeepers of the liver microenvironment ( 20 ). The disrupted intercellular crosstalks between LSECs and other cell types within the sinusoids are involved in the pathogenesis of liver fibrosis ( Du and Wang ).…”