Abstract
Simple SummaryDuring the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development.The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
Highlights
The liver is the main organ regulating blood clearance and metabolism, and as the first organ receiving intestinal blood, it participates majorly in the immune response.The hepatic sinusoid constitutes the microcirculatory bed of the liver, and it is highly specialised to facilitate all liver functions
The hepatic sinusoid is mainly composed of liver sinusoidal endothelial cells (LSECs), which constitute the permeabilized wall of the sinusoid, hepatic stellate cells (HSCs), which are vitamin A-storing pericytes localized in the space of Disse—or the perisinusoidal space, which is the area between hepatocytes and LSECs—and regulate the sinusoidal microvascular tone and synthesize extracellular matrix (ECM), and Kupffer cells (KCs), the liver-resident macrophages
Persistent damage due to disease or exposure to toxic substances induces the deregulation of these cell types, which switch from maintaining proper liver homeostasis to a proinflammatory and profibrotic phenotype that further compromises liver function
Summary
The liver is the main organ regulating blood clearance and metabolism, and as the first organ receiving intestinal blood, it participates majorly in the immune response. As opposed to most other tissues in the body, the liver receives venous blood as an input, arriving through the portal vein, rich in nutrients and carrying approximately 50% of the hepatic oxygen supply This blood mixes with the oxygenated arterial blood arriving from the hepatic artery and flows through the sinusoid, draining into the vena cava [1] (Figure 1). Under persistent damage, such as chronic hepatitis B or C, chronic alcohol and/or high fat diet consumption, among others [3], the specialized phenotype of all hepatic cell types is impaired This induces persistent inflammation and wound healing mechanisms which, over time, will trigger the formation of scar tissue and hemodynamic alterations in the liver [4], leading to cirrhosis and hepatocellular carcinoma (HCC), which is currently the eleventh most common cause of death globally [5]. A wide and deep understanding of these molecular mechanisms has been pursued in recent years in order to develop effective strategies and ameliorate PH by targeting its primary cause: altered liver microvascular circulation
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