Portal fibroblasts

Abstract

Portal fibroblasts are an important yet often overlooked nonparenchymal cell population in the liver. They are distinct from hepatic stellate cells, yet like stellate cells differentiate in the setting of chronic injury to fibrogenic myofibroblasts, playing an important role in collagen production in the fibrotic liver. Portal fibroblasts (PFs) are located adjacent to bile duct epithelia and thus play a particularly significant role in biliary fibrosis. New data suggest that they may also have key functions independent of fibrogenesis. This review addresses the definition and characteristics of PFs as well as their signaling pathways, interactions with the biliary epithelium, and contributions to liver pathobiology. Conclusion: PFs are an important and multifunctional nonparenchymal cell population in need of further study.

Cellular and molecular mechanisms in liver fibrogenesis

“…In the last two decades experimental and clinical studies have provided considerable evidence indicating that liver fibrosis and, possibly, even cirrhosis should be considered as potentially reversible processes [1,3,6,11]. As outlined by several researchers in authoritative reviews [1,3,6,11], critical issues in fibrosis and cirrhosis reversal, providing that the etiological agent or condition may be eliminated or efficiently counteracted by means of selective therapy, are represented by the induction of hepatic MFs apoptosis and by an increased degradation of excess ECM.…”

“…As outlined by several researchers in authoritative reviews [1,3,6,11], critical issues in fibrosis and cirrhosis reversal, providing that the etiological agent or condition may be eliminated or efficiently counteracted by means of selective therapy, are represented by the induction of hepatic MFs apoptosis and by an increased degradation of excess ECM. This has opened the way to experimental studies designed to characterize more selective therapeutic strategies to target either hepatic MFs, specific ligand-receptor interactions or pro-fibrogenic signaling pathways, in order to switch on or at least potentiate fibrosis reversal.…”

“…In addition, resolution of liver fibrosis has been reported to be accompanied by a switch in the TIMP/MMP balance, with the mentioned reduction in the hepatic TIMP expression being associated with an increase in the hepatic metalloprotease (MMP) expression [1][2][3][4][5]. A complementary key issue in fibrosis reversal is represented by infiltration of the hepatic scars by bone-marrow -derived macrophages, which are rich source of MMPs that are critical to the successful regression in hepatic scar, with macrophages being then able to promote both liver fibrosis formation and fibrosis regression [1][2][3][4][5][6]11].…”

“…When trying to synthetically describe this first stage (see Figure 1), a number of concepts should be taken in mind [1][2][3][4][5][6]: i) perpetuation of hepatic injury, a typical hallmark of CLD progression, depends not only from chronic exposure to the specific etiology but also results from chronic injury itself and chronic inflammatory response, through a number of final mediators (with a prevailing role of reactive oxygen species or ROS); ii) chronic activation of inflammatory response and recruitment/activation of cells involved in either innate or acquired immunity can progressively result in what one may define pro-fibrogenic environment, in which synthesis and release of growth factors, cytokines, chemokines, ROS and other mediators will from one side impair significantly hyperplasia/regeneration of hepatic tissue and on the other side will favor chronic activation of wound healing and fibrogenesis; iii) the profibrogenic environment will, in turn, lead to persistent activation of MF-like cells and then increased deposition of ECM components which is paralleled by altered/inefficient remodeling; iv) emerging evidence suggests a major role for hypoxia and angiogenesis in sustaining and, likely, driving fibrogenesis as well as vascular changes that become more and more relevant during CLD progression; v) liver fibrosis in this first stage is potentially reversible, as shown by both experimental and clinical studies; fibrosis reversion may depend on the removal of exposure to the specific etiology or to effective therapy.…”

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

“…Among these populations, PFs have been well documented to play a role as myofibroblast precursors, particularly in conditions of biliary fibrosis caused by cholestatic liver injury 9, 10. PFs are defined as a non‐HSC fibroblast population that can be found in the periportal mesenchyme surrounding the bile ducts; they are considered to be a heterogeneous population 11.…”