Overview

Liver microcirculation plays an essential role in the progression and aggravation of chronic liver disease. Hepatic sinusoid environment, mainly composed of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells, intimately cooperate to maintain global liver function and specific phenotype of each cell type. However, continuous liver injury significantly deregulates liver cells’ protective phenotype, leading to parenchymal and non-parenchymal dysfunction. Our group is focused on the research of the cellular and molecular processes that mediate hepatic microcirculatory injury and the intercellular communications within the liver, to ultimately develop new therapeutic strategies to ameliorate liver diseases.

The liver sinusoid 

The hepatic sinusoid represents a well-organized vascular matrix that provides the structural and biochemical environment in which non-parenchymal liver cells live and communicate. The space of Disse separates sinusoidal cells from parenchymal cells and contains extracellular matrix (ECM) components. Thus, the liver microenvironment can be described as a multidirectional interaction complex (cell-matrix-cell) organized to manage the delivery of molecular signals, where every piece has a crucial role. It is due to this particular structure that hepatic cells, composed mainly of hepatocytes, liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and Kupffer cells (KC), precisely communicate with each other.

Chronic liver injury 

In response to hepatic injury, LSEC become rapidly dysregulated and start de-differentiation towards a “capillarized” phenotype. This is accompanied by the production and release of soluble factors that rapidly travel to neighbouring cells affecting their phenotype. In parallel, exogenous hepatic injury significantly modifies hepatocytes transcriptional programs promoting their proliferation and death. Hepatocyte apoptosis results in the formation of apoptotic bodies that once captured by the non-parenchymal cells (HSC and KC) contribute to their activation. In turn, HSC begin to proliferate, contract and deposit elevated amount of extracellular matrix in the hepatic parenchyma, contributing to the stiffening of the organ and perturbing all cellular functions. Interestingly, collagen accumulation in the space of Disse may contribute to the loss of endothelial fenestrations, aggravating hepatic fibrosis. Thus, a self-perpetuating cycle between collagen-producing activated HSC and capillarized LSEC stimulate each other, further contributing to liver fibrosis (Fig. 1).

Fig. 1. Sinusoidal crosstalk during chronic liver injury. Initial dysregulation in functional hepatocytes (fHep) and liver sinusoidal endothelial cells (LSEC) due to liver damage lead to complex paracrine interactions (red arrows) with quiescent hepatic stellate cells (qHSC) and Kupffer cells (KC), ultimately creating a dysfunctional sinusoidal microenvironment composed by dysfunctional LSEC (dxLSEC), activated HSC (aHSC), activated KC (aKC) and dysfunctional and necroptotic hepatocytes (dxHep). Phenotypic characteristics of each cell type are progressively lost during the progression of the liver disease, and new pathologic properties appear. REF: Marrone G, Shah V and Gracia-Sancho J. Journal of Hepatology 2016;65(3):608-17.

Publications

Vilaseca M*, Guixé-Muntet S*, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therapeutic Advances in Gastroenterology 2018; in press.

Gracia-Sancho J, Guixé-Muntet S. The many-faced role of autophagy in liver diseases. Journal of Hepatology 2018;68(3):593-594.

Guixé-Muntet S, Gracia-Sancho J. Autophagy and Liver Disease. In book: Autophagy and Cardiometabolic Diseases. 2018; DOI:10.1016/B978-0-12-805253-2.00017-1.

Guixé-Muntet S, de Mesquita FC, Vila S, Hernández-Gea V, Peralta C, García-Pagán JC, Bosch J, Gracia-Sancho J. Cross-talk between autophagy and KLF2 determines endothelial cell phenotype and microvascular function in acute liver injury. Journal of Hepatology 2017;66(1):86-94.

Marrone G, Shah V and Gracia-Sancho J. Journal of Hepatology 2016;65(3):608-17.