Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?

Abstract

The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.

Uncorrelated healing response of tendon and ear injuries in MRL highlight a role for the local tendon environment in driving scarless healing

“…This glycoprotein has been identified to modulate the structural environment of regeneratively healing fetal skin and adult liver wounds (16,32). Similar to the results found in MRL/MpJ, early increases in HA in the peri-cellular and extra-cellular space during early fetal healing modulates the cell–matrix relationship, and can increase availability and efficiency of receptor-ligand interactions necessary to modulate cell behavior and induce regeneration (15,16,32).…”

“…This glycoprotein has been identified to modulate the structural environment of regeneratively healing fetal skin and adult liver wounds (16,32). Similar to the results found in MRL/MpJ, early increases in HA in the peri-cellular and extra-cellular space during early fetal healing modulates the cell–matrix relationship, and can increase availability and efficiency of receptor-ligand interactions necessary to modulate cell behavior and induce regeneration (15,16,32). In adulthood, however, prolonged increases in HA, similar to what is seen in scar-mediated healing C57Bl/6 tendons at 4-week post-injury, have been implicated in lung, liver, and kidney fibrosis labeling this glycoprotein as a marker for disease progression (33–35).…”

“…Namely, Hyaluronan (HA), a key structural glycoprotein of the ECM, has been shown to modulate the local inflammatory healing phase, provide structural matrix integrity, and regulate availability and activation of growth factors such as TGF-β, FGF, and PDGF during the regenerative healing response of these tissues (14–16). These key growth factors are upregulated during repair and play a major role in modulating cell proliferation, angiogenesis and fibrosis.…”

Pathogenesis of Nonalcoholic Steatohepatitis

“…Studies of NAFLD progression have found that the severity of liver fibrosis is the only feature of NASH that independently predicts liver-related morbidity and mortality 11 . Further research is needed to determine why progressive scarring develops in only some patients with NASH, define the mechanisms that shift effective regeneration to pathologic scarring 42,43 , and determine how wound-healing responses might be modulated to heal lipotoxicity without scar 44 .…”

Human fetal wound healing: a review of molecular and cellular aspects

“…Other growth factors such as growth factor derived from platelets (PDGF) and fibroblast growth factor (FGF) also exhibit temporal and spatial differences in fetal wound healing [32]. Exogenous PDGF (mitogen and chemotactic factor for fibroblasts) induces fibrosis in fetal wounds in rabbits [33].…”