Liver sinusoidal endothelial cell: An important yet often overlooked player in the liver fibrosis

Abstract

Liver sinusoidal endothelial cells (LSECs) are liver-specific endothelial cells with the highest permeability than other mammalian endothelial cells, characterized by the presence of fenestrae on their surface, the absence of diaphragms and the lack of basement membrane. Located at the interface between blood and other liver cell types, LSECs mediate the exchange of substances between the blood and the Disse space, playing a crucial role in maintaining substance circulation and homeostasis of multicellular communication. As the initial responders to chronic liver injury, the abnormal LSEC activation not only changes their own physicochemical properties but also interrupts their communication with hepatic stellate cells and hepatocytes, which collectively aggravates the process of liver fibrosis. In this review, we have comprehensively updated the various pathways by which LSECs were involved in the initiation and aggravation of liver fibrosis, including but not limited to cellular phenotypic change, the induction of capillarization, decreased permeability and regulation of intercellular communications. Additionally, the intervention effects and latest regulatory mechanisms of anti-fibrotic drugs involved in each aspect have been summarized and discussed systematically. As we studied deeper into unraveling the intricate role of LSECs in the pathophysiology of liver fibrosis, we unveil a promising horizon that pave the way for enhanced patient outcomes.

Keywords: Capillarization; Fenestrae; Intercellular communication; Liver fibrosis; Liver sinusoidal endothelial cells.

Figure 1.

Mechanisms of LSEC angiogenesis and the related pharmacological intervention in the process of liver fibrosis. VEGF and HIF-1α were the two most crucial pathways in the process of LSEC angiogenesis. Treatments such as lenvatinib, levistilide A, olmesartan, TMP and FZHY could inhibit the VEGF pathway, exerting anti-angiogenic effects. Oroxylin A, CFE, curcumol and TMP could reverse the activation of angiogenesis caused by the HIF-1α pathway. Angiogenesis mediated by DLL4/Notch pathway was suppressed by miR-30c. AKAP12 inhibited EDN1-mediated angiogenesis. Olmesartan inhibited PDGF-mediated angiogenesis. Levistilide A, CU06-1004, and sulodexide could reduce LSEC angiogenesis by inhibiting the expression of CD31 or CD34. LSEC, liver sinusoidal endothelial cell; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia inducible factor-1α; TMP, tetramethylpyrazine; DLL4, delta-like ligand 4; PDGF, platelet-derived growth factor.

Figure 2.

Communication among LSECs, HSCs and hepatocytes around the space of Disse during liver fibrosis. The expression of Zeb2 and eNOS in LSECs maintained HSC quiescence. Arin interacted with EZH2 to maintain HSC quiescence and hepatocyte proliferation through releasing WNT2A and HGF in paracrine manners. When stimulated by CD147, hepatocytes promoted LSEC capillarization through the PI3K/AKT/ VEGF-A/VEGFR2 axis. PDGF-BB stimulated by CXCR4, TGF-β stimulated by S1PR2 or PLK, JAM-A and A-FABP and were released from LSECs in paracrine manners and then activated HSCs. Exosomal SPHK1 from LSECs activated HSCs through vesicle transport. VCAM1 derived from LSECs stimulates HSC activation through Hippo and YAP1 pathways. Notch and BRG1 inhibit eNOS, reducing the bioavailability of NO and losing the ability to suppress HSCs. A-FABP, adipocyte fatty acid binding protein; AKT, AKT serine/threonine kinase; BRG1, brahma-related gene 1; CXCR4, C-X-C chemokine receptor 4; eNOS, endothelial nitric oxide synthase; EZH2, enhancer of zeste homolog 2; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; IVA-PLA2, group IVA phospholipase A2; JAM-A, junctional adhesion molecule A; LSEC, liver sinoidal endothelial cell; NO, nitric oxide; PDGF-BB, platelet-derived growth factor-BB; PDGFR-β, platelet-derived growth factor receptor β; PI3K, phosphoinositide 3-kinases; PLK, polo-like kinase; S1PR2, sphingosine-1-phosphate receptor 2; SPHK1, sphingosine kinase 1; TGF-β, transforming growth factor beta; VCAM1, vascular cell adhesion molecule 1; VEGFA, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2; WNT2A, WNT family member 2a; YAP1, yes-associated protein 1.

Figure 3.

The interaction among LSECs with other cells. LSECs promote the transformation of macrophages into KCs through the binding of DLL4 to Notch receptor in macrophage. LSECs regulate the recruitment of KCs by secreting MMPs and TIMPs. The ligands such as ICAM-1 and VCAM-1 in KCs bind with the integrins on KCs and participate in the direct adhesion process between KCs and LSECs. TGF-β, DLL4, and LXR ligand in LSECs can interact with receptors such as TGFβR, Notch, and LXR in KCs, then maintaining the identity of KCs. Moreover, LSECs can secrete pro-inflammatory mediators to activate KCs. Th 1 and Th2 cells promote or inhibit angiogenesis in LSECs through the Rho-ROCK-myosin pathway. LSEC, liver sinusoidal endothelial cell; DLL4, delta-like ligand 4; VCAM1, vascular cell adhesion protein 1; TGF, transforming growth factor.

Figure 4.

Multiple pathways by which LSECs contribute to the progression of liver fibrosis. During the process of liver fibrosis, LSECs was dedifferentiated, which was characterized as capillarization, defenestration, and phenotype transition. In addition, the intracellular NO/ROS homeostasis and the vascular secretion pathways were remodeling. Further, the impaired communication of LSECs along with several cell types aggravated ECM deposition and the development of liver fibrosis. HSC, hepatic stellate cell; LSEC, liver sinusoidal endothelial cell; NO, nitric oxide; ROS, reactive oxygen species; ECM, extracellular matrix.