Emerging concepts in biliary repair and fibrosis

Abstract

Chronic diseases of the biliary tree (cholangiopathies) represent one of the major unmet needs in clinical hepatology and a significant knowledge gap in liver pathophysiology. The common theme in cholangiopathies is that the target of the disease is the biliary tree. After damage to the biliary epithelium, inflammatory changes stimulate a reparative response with proliferation of cholangiocytes and restoration of the biliary architecture, owing to the reactivation of a variety of morphogenetic signals. Chronic damage and inflammation will ultimately result in pathological repair with generation of biliary fibrosis and clinical progression of the disease. The hallmark of pathological biliary repair is the appearance of reactive ductular cells, a population of cholangiocyte-like epithelial cells of unclear and likely mixed origin that are able to orchestrate a complex process that involves a number of different cell types, under joint control of inflammatory and morphogenetic signals. Several questions remain open concerning the histogenesis of reactive ductular cells, their role in liver repair, their mechanism of activation, and the signals exchanged with the other cellular elements cooperating in the reparative process. This review contributes to the current debate by highlighting a number of new concepts derived from the study of the pathophysiology of chronic cholangiopathies, such as congenital hepatic fibrosis, biliary atresia, and Alagille syndrome.

Keywords: cholangiopathies; ductular reaction; hepatic progenitor cells; macrophages; myofibroblasts.

Fig. 1.

Biliary repair and fibrosis in congenital hepatic fibrosis. Portal inflammation is driven by the secretion of different chemokines (CXCL1, CXCL10, and CXCL12) by fibrocystin (FPC)-defective cholangiocytes due to an overactivation of β-catenin signaling promoting macrophage recruitment from the circulating monocyte compartment. In turn, macrophage-derived cytokines (TNFα in the first 6 mo and in conjunction with TGFβ afterward) induce upregulation of integrin αvβ6, an activator of latent TGFβ1, in cholangiocytes. In the early phase of fibrosis (1–6 mo), α-smooth muscle actin (α-SMA)⁺ cells are scarce, and the peribiliary infiltrate is dominated by M1 macrophages. In the 2nd phase (>6 mo), macrophages switch to an M2 phenotype paralleled by an increased recruitment of activated portal myofibroblasts (MFs). In this phase, portal fibrosis extends and associates with portal hypertension. FPC-KO, fibrocystin knockout.

Fig. 2.

Biliary repair and fibrosis in biliary atresia. IL-33 abundantly secreted by cholangiocytes stimulates accumulation of ILC2 (innate lymphoid cells). Once recruited in the peribiliary area, ILC2 release large amounts of IL-13, which exerts potent mitogenic effects on cholangiocytes, thus promoting and sustaining biliary hyperplasia. Furthermore, in concert with other factors released in the periductal area as a consequence of duct obstruction [TGFβ1, osteopontin (OPN), and bile acids], IL-13 stimulates activation of HSC, leading to extensive peribiliary fibrosis and progressive ductal stricturing. RRV, rhesus rotavirus type A.

Fig. 3.

Morphogenetic signals regulating biliary repair. The reactivation of morphogenetic pathways involved in biliary development [Notch, Hedgehog, Wnt/β-catenin, and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ)] regulates activation of hepatic progenitor cells (HPC) and the ability of reactive ductular cells (RDC) to build up functionally active tubular structures. See text for details. EMT, epithelial-to-mesenchymal transition; IHH/SHH, Indian Hedgehog/Sonic Hedgehog; Ptc, patched; Smo, smoothened; NICD, Notch intracellular domain; ADAM/TACE, a disintegrin and metalloproteinase domain-containing protein 10/tumor necrosis factor-α-converting enzyme; Dvl, disheveled; IHBC, intermediate hepato-biliary cells; TCF/LEF, T cell factor/lymphoid enhancer factor; TEADs, TEA domain transcription factors.

Fig. 4.

Biliary repair and fibrosis in Alagille syndrome. If Notch signaling is defective, then activation of HPC following biliary damage by Jagged1-expressing PMFs, which instead forms RDC aimed at restoring tubular biliary structures (top), is forced toward the hepatocyte lineage, leading to IHBC accumulation (bottom). This abnormal mechanism of biliary repair has consequences on liver fibrogenesis; whereas the reduced no. of RDC is associated with scarce deposition of fibrotic tissue in the peribiliary area, the increased no. of IHBC is associated with an intralobular, pericellular fibrosis, reproducing the “chicken wire” pattern.