Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence

Abstract

Capillarization precedes hepatic fibrosis. We hypothesize that capillarization of sinusoidal endothelial cells (SEC) is permissive for hepatic stellate cell (HSC) activation and therefore permissive for fibrosis. We examined whether freshly isolated SECs prevent activation of HSCs and promote reversion to quiescence, and whether this effect was lost in capillarization. HSCs were cultured alone or co-cultured with differentiated or capillarized SECs. Results: Co-culture with freshly isolated SECs markedly decreased HSC activation after 3 days in culture, but co-culture with capillarized SEC had no effect.

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

“…Hepatic VEGF mRNA expression is significantly increased in the rat model in parallel with sinusoidal damage (44) and serum VEGF increase correlates with the development of SOS in patients after hematopoietic stem cell transplantation (45). VEGF plays a major role in maintaining SEC differentiation (46)(47)(48). The increased expression of VEGF could therefore be a response to endothelial barrier disruption or to cellular hypoxia following SOS.…”

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…NO production usually decreases, leading to an increasing intrahepatic pressure due to an inability to maintain intrasinusoidal autoregulation by vasodilatation [1,17]. In addition, decreased NO production activates a contractile phenotype of HSC, inducing extracellular matrix production and migratory capacity [18,19]. Finally, recent studies revealed the importance of angiogenesis in the process of fibrogenesis and their interdependency [12,20].…”

“…However, as described for SEC, HSC can undergo dramatic phenotype transformation in the context of liver injury: a decrease in NO production by SEC, which normally induces HSC quiescence, leads to HSC activation characterized by enhanced contractility, increased migratory capacity, deposition of extracellular matrix components such as fibronectin and collagen I or III, upregulation of smooth muscle alpha actin (a-SMA), and increased release of autocrine and paracrine factors. Besides this canonical NO pathway for quiescence and activation of HSC, [18,19] several other soluble factors from surrounding cells (such as hepatocytes, Kupffer-cells, and lymphocytes) play an important role in HSC activation [26]. Interestingly, studies of different extracellular matrices have revealed that matrix stiffness itself is a key determinant of HSC activation, although involved proteins and receptors have not been identified so far [27].…”

“…Besides the canonical pathway of constitutive expression of NO in SEC and its role in the quiescence of HSC [1,19], numerous paracrine and autocrine factors and SEC/HSC crosstalk mechanisms have been identified and discussed in other reviews [1,9,20,21]. Therefore, the following examples of intercellular communication are used illustratively and do not claim to provide a complete overview.…”

“…Given the paracrine effect of NO on smooth muscle cells and HSC and its autocrine effect on SEC, shear stress leads to a decrease in intrahepatic resistance as a response to increased blood flow, and maintains SEC phenotype [8]. By release of NO from SEC, the latter not only prevent HSC activation, they also promote reversion to quiescence [19]. Thus, reduced NO not only increases intrahepatic resistance, it also plays an important role in the early steps of liver fibrosis [2].…”