Sinusoidal communication in liver fibrosis and regeneration

Abstract

Cellular crosstalk is a process through which a message is transmitted within an individual cell (intracellular crosstalk) or between different cells (intercellular crosstalk). Intercellular crosstalk within the liver microenvironment is critical for the maintenance of normal hepatic functions and for cells survival. Hepatic cells are closely connected to each other, work in synergy, and produce molecules that modulate their differentiation and activity. This review summarises the current knowledge regarding paracrine communication networks in parenchymal and non-parenchymal cells in liver fibrosis due to chronic injury, and regeneration after partial hepatectomy.

Effects of aging on liver microcirculatory function and sinusoidal phenotype

“…Further analysis revealed a global deregulation in the hepatic endothelial phenotype in aging as demonstrated by significant decrease in key vasodilatory pathways, including nitric oxide and heme oxygenase, increment in intracellular inflammation and oxidative stress, and reduction in the expression of functional and angiocrine markers such as stabilin‐2, CD32b (Xie et al, 2013), and VEGFR2 (Carpenter et al, 2005). Reduction in intrahepatic nitric oxide availability is of relevance considering its importance modulating the vascular tone (Gracia‐Sancho, Maeso‐Diaz, Fernandez‐Iglesias, Navarro‐Zornoza, & Bosch, 2015; Hori, Wiest, & Groszmann, 1998), exerting anti‐inflammatory effects (Iwakiri & Kim, 2015), and maintaining neighboring cells phenotype (Marrone et al, 2016; Xie et al, 2013). Reduced nitric oxide bioavailability might, at least in part, derive from diminished eNOS activity, which may be due to reduced VEGF‐p‐eNOS pathway (Kroll & Waltenberger, 1998), and from increased scavenging due to elevated oxidative stress (Gracia‐Sancho et al, 2008).…”

“…Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and Kupffer cells (KC) are the major components of the hepatic sinusoid, which collaborate to maintain the integrity and functionality of the unique liver microcirculatory system (Marrone, Shah, & Gracia‐Sancho, 2016). LSEC are a very specialized fenestrated endothelial cell forming the capillary bed of the sinusoids, being separated from hepatocytes through the space of Disse.…”

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…In response to liver injury, HSCs are activated through paracrine or autocrine mechanisms that involve platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), endothelin-1, eicosanoid derivatives, and extracellular matrix components such as fibronectin [42]. Upregulation of the smooth muscle proteins actin and myosin increases the contractility of activated HSCs, further restricting sinusoidal flow [43]. Experimental observations in cirrhotic rat livers suggest that this reversible component accounts for 20-30% of IHVR [44].…”

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…In NASH, iterative deleterious signals activate LSECs and HSCs (8,9), thereby compromising ECM component production and turnover. The ensuing fibrotic process functionally and structurally alters the intrahepatic vasculature, and a complex cascade of events can ultimately lead to cirrhosis and its complications, including increased death rates (10,11).…”