Hepatic fibrosis: a convergent response to liver injury that is reversible

Graphical Abstract

Deposition of extracellular matrix accompanies wound repair and regeneration following liver injury; however, repeated injury from chronic viral hepatitis (HBV, HCV etc.), Western diet, alcohol, environmental toxins, and/or immune diseases may provoke a progressive fibrotic response characterized by excess collagen accumulation. Hepatic fibrosis progressively restricts normal liver regeneration, thus increasing the risk of liver failure. Hepatic fibrosis also generates a permissive micro-environment for the development of liver cancer through mechanisms that are not fully elucidated [1]. Importantly, hepatic fibrosis can resolve once injury subsides, as seen in HCV patients successfully treated with antiviral therapy, with the level of resolution inversed correlated with disease severity [2].

Hepatic stellate cells (HSCs) are the main collagen-producing cells in the liver and represent the central driver of hepatic fibrosis [3]. Under healthy conditions, quiescent HSCs serve as the main retinyl ester storage site in the body, which are clearly visible as fat droplets in the cytoplasm [3]. Liver regeneration studies using the partial hepatectomy model have indicated a pro-regenerative function for HSCs, althrough underlying mechanisms that are still being explored. These mechanisms may be linked to the secretion of mitogenic cytokines (e.g, hepatocyte growth factor and vascular endothelial growth factor) [4, 5]. Knowledge about homeostatic functions of quiescent HSCs will likely expand as more tools become available that can selectively alter or delete stellate cells in animal models. A number of transcription factors preserve the quiescent HSC phenotype, with some also playing critical roles in development, such as GATA4/6, LHX2, TCF21, while others may regulate the adipocyte-like state of HSCs, including PPARγ, GR, and RARβ [6, 7].

When the liver is injured, DAMPs (Damage-Associated Molecular Patterns) / PAMPS (Pathogen-Associated Molecular Patterns) released from damaged hepatocytes trigger the trans-differentiation of the retinoid droplet-storing quiescent HSCs into myofibroblast-like, activated HSCs that are: 1) highly fibrogenic, through enhanced TGFβ1 (transforming growth factor beta 1) signaling; 2) proliferative and migratory, through PDGFRβ (platelet derived growth factor receptor beta) signaling; 3) contractile, through activation of ET-1 (endothelin 1) signaling; and 4) pro-inflammatory, through cross-talk with monocyte-derived macrophages [3]. Drivers of the activated HSC gene expression program also include epigenetic modifiers such as BRD4, and master regulators of cell proliferation genes including AP-1 (Activator Protein 1) and YAP/TAZ (yes-associated protein 1/Tafazzin), among others [3, 7].

As liver injury subsides, activated HSCs are removed from the liver by undergoing either apoptosis or deactivation [8, 9]. Apoptosis of activated HSCs is a regulated process that balances intrinsic and extrinsic, pro-death versus pro-survival signals that converge on members of the BCL-2 (B-cell lymphoma 2) family [10]. Much less is known about what regulates deactivation of HSCs, which is an important priority for future studies. Specifically, it is unclear if HSC deactivation is an active process (i.e. regulated by specific signaling pathways), as suggested by a recent study demonstrating delayed fibrosis resolution in PPARγ and GATA6 knockout animals [7], or a passive process (i.e. simply the down-regulation of the same signaling pathways that maintain activated HSCs). It is also unknown if or how deactivated HSCs contribute to the increased collagen degradation, cellular senescence, and decreased inflammation that accompany fibrosis resolution, or if deactivated HSCs execute a similar gene expression program controlled by the same transcription factors as quiescent stellate cells.

In summary, HSCs are established as the main drivers of hepatic fibrosis, but much remains to be discovered about their contribution to liver homeostasis, cancer development, and fibrosis resolution.