Review
The role of Hedgehog signaling in fibrogenic liver repair

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Abstract

Repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. Our studies demonstrate that the fates of such cells are dictated, at least in part, by Hedgehog, a fetal morphogenic pathway that was once thought to be active mainly during embryogenesis. Studies of injured adult human and rodent livers demonstrate that injury-related activation of the Hedgehog pathway modulates several important aspects of repair, including the growth of hepatic progenitor populations, hepatic accumulation of myofibroblasts, repair-related inflammatory responses, vascular remodeling, liver fibrosis and hepatocarcinogenesis. These findings identify the Hedgehog pathway as a potentially important target for biomarker development and therapeutic manipulation, and emphasize the need for further research to advance knowledge about how this pathway is regulated by and interacts with other signals that regulate adult liver repair.

Introduction

The adult liver is comprised largely of epithelial cells and mesenchymal cells similar to the skin, intestine, lung, and glandular tissues like the pancreas. In all of these organs, the ultimate outcome of epithelial injury is dictated by repair. Successful liver repair results in replacement of dead or damaged hepatic epithelial cells with healthy new epithelial cells, i.e., liver regeneration. Regenerative responses differ depending on the severity and chronicity of liver injury. For example, it has long been believed that residual mature hepatocytes and cholangiocytes proliferate to restore liver mass after acute partial hepatectomy (Grisham, 1962). However, liver progenitors are thought to play a critical role in the repair of chronically injured livers (Falkowski et al., 2003). Repair of liver injury also variably involves changes in mesenchymal cells. Presumably, alterations in hepatic “stromal” cells in some way contribute to epithelial repair. However, they may also lead to hepatic inflammation, vascular remodeling, and fibrosis, and result in hepatic architectural distortion and liver dysfunction, eventually culminating in cirrhosis (Wynn, 2008).

Signal transduction pathways, such as wnt/beta catenin and notch/jagged, that control the viability, proliferation, and differentiation of progenitor cells are known to regulate fetal liver development (Cavard et al., 2008, Lemaigre and Zaret, 2004). These pathways also become activated during various types of liver injury in adults, and are presumed to modulate adult liver repair (Kordes et al., 2009). Consistent with this concept, dysregulation of wnt/beta catenin signaling has been documented in primary liver cancer and is believed to contribute to its pathogenesis (de La Coste et al., 1998, Huang et al., 1999, Suzuki et al., 2002). Our group has been examining another morphogenic signaling pathway, Hedgehog. Although relatively little is known about the role of Hedgehog in fetal liver development, we became interested in this pathway because it controls the viability and fate of progenitors in many tissues, and it was reported that Sonic Hedgehog ligand is expressed by endoderm that has undergone hepatic specification (Bort et al., 2006, Deutsch et al., 2001). Our work in adult liver has proven that several types of cells that reside in healthy adult livers are capable of producing and/or responding to Hedgehog ligands, shown that the pathway is activated in many types of acute and chronic liver injury, and demonstrated roles for Hedgehog pathway activation in several of the tissue responses that occur during adult liver repair, including expansion of liver progenitor populations, myofibroblast accumulation and fibrogenesis, repair-related inflammation, vascular remodeling, liver regeneration and carcinogenesis. The goal of this review is to summarize this new evidence and suggest a new model that helps to explain how various aspects of liver repair are coordinated by Hedgehog-regulated signals.

Section snippets

Overview of the Hedgehog pathway

The Hedgehog (Hh) pathway, originally identified in Drosophila (Hooper and Scott, 2005, Lee et al., 1992, Schuske et al., 1994), is a highly conserved signaling pathway which orchestrates multiple aspects of embryogenesis, development and tissue remodeling in a wide spectrum of systems (Beachy et al., 2004, Berman et al., 2003, Ingham and McMahon, 2001, van den Brink, 2007). This usually occurs by autocrine/paracrine signaling and aims to control the size and localization of Hh-responsive cell

Hedgehog signaling in adult liver repair: general concepts

Adult hepatic damage evokes an intricate wound-healing response aimed to reconstitute the normal structure and function of injured livers. As in many other tissues, this complex repair process involves the post-natal reactivation of mechanisms that regulate tissue construction during development. Several types of cells in adult livers are capable of producing and/or responding to Hh ligands. However, expression of Hh ligands and Hh-target genes, such as Gli1 or Gli2, is barely detectable in

Hedgehog pathway activation and liver progenitors

Progenitor populations in many tissues are enriched with Hh-responsive cells and Hh ligands generally enhance the growth of such progenitors by inhibiting apoptosis and/or enhancing proliferative activity (Sicklick et al., 2006b, Jung et al., 2007, Yang et al., 2008). We reported that human embryonic stem cells that had been specified to undergo hepatic differentiation, as well as more-differentiated EpCam-expressing liver progenitors from human fetal livers, were Hh-responsive. Both cell types

Hedgehog pathway activation and repair-related inflammation

Hh pathway activation stimulates immature ductular cells to produce various chemokines, including chemoattractants for monocytes, neutrophils, and various types of T lymphocytes, including natural killer T (NKT) cells (Omenetti et al., 2009). In order to evaluate the potential significance of this response, we have examined Hh-regulation of CXCL16, the chemokine that recruits NKT cells to the liver. We proved that ductular cell expression of CXCL16 is Hh-dependent and showed that the resultant

Hedgehog pathway activation and liver fibrosis

Myofibroblasts are the major source of fibrous matrix that accumulates during chronic liver injuries that result in cirrhosis. Liver myofibroblasts may be derived from several sources, including circulating bone marrow-derived monocytes/fibrocytes, epithelial-to-mesenchymal transition (EMT) of certain types of liver epithelial cells, and myofibroblastic transformation of resident hepatic stellate cells. The latter process is generally believed to be the predominant source of myofibroblasts in

Hedgehog pathway activation and vascular remodeling

Cirrhosis is characterized by changes in hepatic sinusoidal architecture together with extrahepatic vasculature rearrangement (Friedman, 2008). Several types of cells that reside near sinusoidal endothelial cells are capable of generating Hh ligands, including injured hepatocytes, activated HSC, liver progenitors, and certain types of resident lymphocytes. The Hh pathway is a key regulator of vascular remodeling during development (Vokes et al., 2004), while PDGF-BB (which activates Hh

Hedgehog pathway activation and carcinogenesis

Hh pathway activation has been demonstrated in many types of cancer (Beachy et al., 2004). In some tumors, this results from activating mutations in smoothened or gli family members (Toftgard, 2000, Romer and Curran, 2005, Saldanha, 2001, Daya-Grosjean and Couve-Privat, 2005). However, in others enhanced Hh signaling is explained by epigenetic events that silence Hhip or that increase production of Hh ligands (Freeman et al., 2009). Beachy et al. (2004) demonstrated excessive Hh signaling in

Conclusions

Recent evidence suggests that repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. The fates of such cells are dictated, at least in part, by fetal morphogenic pathways which were once thought to be active mainly during embryogenesis, such as Hedgehog. Emerging data from studies of injured adult human and rodent

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