Communication initiated by hepatocytes: The driver of HSC activation and liver fibrosis

Abstract

Liver fibrosis (LF) refers to the excessive deposition and abnormal distribution of the extracellular matrix (ECM) caused by acute or chronic liver injury, which affects the prognosis of liver diseases. Activated HSCs play a central role in LF through their ability to differentiate into myofibroblasts (MFBs) and secrete ECM. Intercellular communication within the liver is important for HSC activation and LF, whether in the initial or persistent stage. Hepatocytes (HCs), the most abundant cell type in the liver, are closely related to hepatic nutrition metabolism and detoxification. Moreover, HC damage is the initiating factor of LF, and interactions between HCs and HSCs may be the most critical event involved in the process of LF. This article reviews the intercellular communication between HCs and HSCs based on paracrine effects, extracellular vesicles, and inflammasomes, which is expected to lead to the development of effective antifibrotic strategies.

Keywords: HSC; extracellular vesicle; hepatocyte; inflammasome; intercellular communication; liver fibrosis; paracrine.

Graphical abstract

FIGURE 1

Functions and characteristics of hepatocyte-mediated intercellular interactions in the process of liver fibrosis. At the initial stage of fibrogenesis, HCs can directly establish communication with HSCs in response to liver injury stimuli. Owing to the persistent damage, HCs further interact with adjacent other types of liver cells, influencing the overall microenvironment and thereby causing the continuous activation of HSCs and the aggravation of liver cirrhosis. This picture was created by figdraw.com. Abbreviations: ALD, alcoholic liver disease; BEC, biliary epithelial cell; HC, hepatocyte; HPC, hepatic progenitor cell.

FIGURE 2

Schematic diagram of HC-derived EVs for regulating HSC activity during LF. The EVs secreted by HCs contain a variety of bioactive contents, which are delivered to quiescent HSCs. Quiescent HSCs then undergo activation through various signaling pathways, strongly affecting LF. Abbreviations: BMP-9, bone morphogenetic protein 9; DLK1, delta-like 1 homolog; EV, extracellular vesicle; HC, hepatocyte; Hh, Hedgehog; LF, liver fibrosis; OPN, osteopontin.

FIGURE 3

HC-released inflammasomes and proinflammatory signals activate HSCs. Upon the action of endogenous or exogenous danger signals, 3 types of inflammasomes (NLRP3, AIM2, and NLRC4) are assembled within HCs through pattern recognition receptors, followed by inflammasome and cytokine production and release through caspase-1–dependent pathways. These proinflammatory mediators further activate HSCs. Abbreviations: AIM2, Absent in Melanoma 2; HC, hepatocyte; NLRC4, Nod-like receptor C4; NLRP3, Nod-like receptor family, pyrin domain-containing 3.

FIGURE 4

Paradigms of paracrine-related intercellular communication between HCs and HSCs. Damaged HCs secrete a variety of active paracrine molecules that affect HSC activation. Moreover, activated HSCs might also aggravate or reduce HC and liver injury through the paracrine effects of signaling molecules. Abbreviation: HC, hepatocyte.