Hepatic Stellate Cell Regulation of Liver Regeneration and Repair

Abstract

The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver regeneration. As our knowledge of the cellular and molecular mechanisms driving hepatic regeneration deepens, the key role of the mesenchymal compartment during the regenerative response has been increasingly appreciated. Single-cell genomics approaches have recently uncovered both spatial and functional zonation of the hepatic mesenchyme in homeostasis and following liver injury. Here we discuss how the use of preclinical models, from in vivo mouse models to organoid-based systems, are helping to shape our understanding of the role of the mesenchyme during liver regeneration, and how these approaches should facilitate the precise identification of highly targeted, pro-regenerative therapies for patients with liver disease.

FIG. 1

Mesenchymal cell heterogeneity and zonation across the hepatic lobule. A) scRNA‐seq experiments have identified three distinct mesenchymal cell populations in homeostatic liver (HSC, hepatic stellate cells; VSMC, vascular smooth muscle cells; PF, portal fibroblasts), with specific markers in human liver (blue) and mouse liver (red). Furthermore, spatial and functional zonation of HSCs across the hepatic lobule has been identified, with HSCs partitioning into portal vein associated HSCs (PaHSCs) and central vein associated HSCs (CaHSCs), again with specific markers. B) Immunofluorescence image of healthy human liver (Dobie et al.^{( 5 )}) demonstrates NGFR positive (red) HSCs around the portal tract (biliary epithelium, green, identified with CK19 staining) and ADAMTSL2 positive (red) HSCs around the central vein. Scale bar, 100 μm. Abbreviations: MYH11, Myosin heavy chain 11; NGFR, Nerve growth factor receptor.

FIG. 2

Phases of hepatic stellate cell activation and resolution. Initiation of hepatic stellate cell (HSC) activation occurs following liver injury, and is driven by a variety of signals^{( 19 )} including reactive oxygen species (ROS), damage associated molecular patterns (DAMPs) and cytokines released from damaged hepatocytes. During the initiation phase, quiescent hepatic stellate cells (qHSCs) transdifferentiate to their activated phenotype (aHSC). The perpetuation phase follows, characterised by a range of HSC phenotypic changes. When injury has subsided, a resolution phase follows, where HSCs undergo apoptosis, become senescent or revert to an inactive phenotype, which is more responsive to subsequent injurious stimuli. Abbreviations: LSEC, liver sinusoidal endothelial cell; KC, kupffer cell; Reln, reelin.

FIG. 3

Functional role of HSCs during the hepatic regenerative response. Activated HSCs (aHSCs) have a number of key functions during the hepatic regenerative response. A) aHSCs produce platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) to upregulate the plasminogen system, enabling ECM remodelling and the release of pre‐formed hepatocyte growth factor (HGF) – the primary mitogen for hepatocytes. B) Production of extracellular matrix (ECM) protects against ongoing damage and provides a ‘scaffold’ for repair. C) aHSCs drive regeneration through autocrine and paracrine signalling. Norepinephrine (NE) enhances the mitogenic effect of HGF. D) aHSCs regulate vessel stabilisation and sinusoidal remodelling through direct and paracrine interactions with liver sinusoidal endothelial cells (LSECs). Abbreviations: TGF ß1, transforming growth factor beta 1; VEGF, vascular endothelial growth factor.