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Review
. 2020 Jan 11;9(1):188.
doi: 10.3390/cells9010188.

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights From the Crosstalk Between Perivascular and Inflammatory Cells in Liver Injury and Repair

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Free PMC article
Review

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights From the Crosstalk Between Perivascular and Inflammatory Cells in Liver Injury and Repair

Lindolfo da Silva Meirelles et al. Cells. .
Free PMC article

Abstract

Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the onset of liver injury. Consequently, HSCs tend to be viewed mainly as myofibroblast precursors in a fibrotic process driven by inflammation. Here, the molecular interactions between liver pericytes and inflammatory cells such as macrophages and neutrophils at the first moments after injury and during the healing process are brought into focus. Data on HSCs and pericytes from other tissues indicate that these cells are able to sense pathogen- and damage-associated molecular patterns and have an important proinflammatory role in the initial stages of liver injury. On the other hand, further data suggest that as the healing process evolves, activated HSCs play a role in skewing the initial proinflammatory (M1) macrophage polarization by contributing to the emergence of alternatively activated, pro-regenerative (M2-like) macrophages. Finally, data suggesting that some HSCs activated during liver injury could behave as hepatic progenitor or stem cells will be discussed.

Keywords: Kupffer cells; hepatic stellate cells; inflammation; liver diseases; liver injury; macrophages; pericytes; perivascular cells.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Interactions between inflammatory cells, perivascular cells, and endothelial cells at the onset and after a liver injury event. (A) Depiction of cells and structures in the liver under normal circumstances; (B) Sequence of events involved in the progression of various types of liver injury. Hepatocyte injury (1) causes release of damage-associated molecular patterns, DAMPs (2). These DAMPs lead to Kupffer cell activation (3) and consequent release of inflammatory mediators (4). Kupffer cells can also be activated by pathogen-associated molecular patterns (PAMPs) derived from pathogenic bacteria or viruses (2′). Inflammatory mediators secreted by activated Kupffer cells trigger activation of endothelial cells and perivascular cells (hepatic stellate cells and, to a lesser extent, non-sinusoidal pericytes) (5). DAMPs and PAMPs also contribute to the activation of endothelial cells and pericytes. Activated endothelial cells promote docking of circulating neutrophils and monocytes, which are stimulated to infiltrate into the tissue owing to the chemo-attractive inflammatory mediators present there (6). Neutrophils secrete reactive oxygen species, ROS (7), while infiltrating monocytes differentiate into proinflammatory (M1) macrophages, which secrete additional inflammatory mediators (8). In the presence of inflammatory mediators, hepatic stellate cells lose their morphological characteristics and, within a few days from the initial injury event, become proliferative cells that produce large amounts of collagen-rich extracellular matrix (ECM), which accumulate in the space of Disse (9) and hinder molecule exchange between the blood and the parenchyma. These cells, also known as myofibroblasts, also contribute to the generation of ROS, which causes further damage in hepatocytes and endothelial cells, and TGF-β, which contributes to modulation of the macrophage phenotype (see text for details). Finally, (10) macrophages that develop along this process (scar-associated macrophages) may take up phenotypes that secrete molecules that help revert fibrosis or may favor perpetuation of fibrosis. During this process, some activated pericytes may give rise to parenchymal cells (see text for details).
Figure 2
Figure 2
Molecular events mediating the interactions between inflammatory cells and perivascular cells soon after a liver injury event and thereafter. (A) Binding of DAMPs or PAMPs to toll-like receptor 4 (TLR4) increases secretion of a number of molecules that are chemotactic to neutrophils and monocytes, which favors their extravasation. (B) M1 macrophages develop from infiltrating monocytes, contributing to an M1 polarization. Neutrophils secrete interleukin 17A (IL-17A), while amphiregulin secreted by M1 macrophages leads to conversion of the latent form of TGF-β into its active form. Binding of IL-17A and TGF-β to their receptors triggers the activation of hepatic stellate cells and other pericytes. (C) Several days after the initial injury event, the number of activated pericytes increases, with consequent production of increased levels of active TGF-β. TGF-β promotes the acquisition of an M2-like phenotype by macrophages that have not acquired an effector phenotype, as well as by M1 macrophages. Macrophage polarization then shifts from M1 to M2-like. (D) During the weeks and months that follow, scar-associated macrophages develop and produce matrix metalloproteinase 7 (MMP7), which converts pro-nerve growth factor (pro-NGF) produced by hepatocytes into NGF. NGF binds to the low-affinity NGF receptor CD271, which is abundant on the surface of myofibroblast-like cells derived from activated pericytes and makes a number of these cells undergo apoptosis.

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