Liver fibrosis: Extracellular vesicles mediated intercellular communication in perisinusoidal space.

Abstract

The complex functional activity of the liver is well-orchestrated thanks to very well-structured crosstalk between all hepatic parenchymal and non-parenchymal cell populations. Paracrine interactions involving extracellular vesicles (EVs) released by various cell types in the liver are vital intercellular communication tools. In normal liver, quiescent hepatic stellate cells (HSCs) released EVs regulate cellular regeneration, survival, cell differentiation, cell migration, and immune responses. After the chronic liver injury, HSCs are activated, acquire myofibroblasts (MFBs) like phenotype and abnormally secrete extracellular matrix proteins that generate fibrous scar. To maintain the pathological status of the injured liver, activated HSCs secrete specific EVs containing profibrotic contents, which interact with hepatocytes, quiescent HSCs, liver sinusoidal endothelial cells (LSECs) and Kupffer cells in the perisinusoidal and sinusoidal spaces. The activated HSCs secrete EVs rich in miR-192, platelet-derived growth factor receptor, and apoptosis signal-regulating kinase 1 to activate quiescent HSCs via the mechanistic target of rapamycin and rho-associated protein kinase 1 signaling axis, known as "horizontal transfer process". In parallel, injured hepatocytes-derived pro-inflammatory miRNAs (miR-19a and -192) and transforming growth factor-β rich exosomes will activate toll-like receptors-9 and -3 on Kupffer cells and HSCs respectively to acquire a fibrogenic phenotype. The Kupffer cells and LSECs released exosome cargos containing miR-103-3p and sphingosine kinase 1, respectively, activate HSCs. The epidermal growth factor-rich exosomes from senescent HSCs increase the viability of hepatoma cells. Thus, perisinusoidal space is a critical microenvironment that coordinates a variety of intercellular signaling mediated by HSCs, hepatocytes, LSECs and Kupffer cells in fibrotic liver diseases.