br Conflict of interest br Introduction br

Conflict of interest
Introduction
Cholangiocytes Cholangiocytes are epithelial rxr receptor lining the intra and extrahepatic ducts of the three-dimensional network of the biliary tree. Biliary cells comprise approximately 3–5% of cells in the liver and are considered as one of the main cell types in liver epithelia. General characteristics of cholangiocytes include a multi-lobulated nucleus, several vesicles at the sub-apical region, tight junctions, high microvilli density, lysosomes, and few mitochondria.Cholangiocytes contain primary cilia that act as cellular antennae for detection and transmission of signals to influence the function of cholangiocytes. When the normal functions of primary cilia are modified or destroyed, it may result in a cholangiopathy.Cholangiocytes can also be classified into two categories according to their size and function. The biliary tree and the functions of cholangiocytes were originally believed to be a passive “plumbing” system whereby the only function was the regulation of bile flow. It is now widely accepted that the biliary tree and cholangiocytes are key regulators of liver homeostasis. In fact, alterations or damage of the biliary tree can induce a ripple effect of cellular crosstalk and signaling pathways, which can progress into chronic liver disease, fibrosis, scarring, and eventual liver failure. The morphological and functional heterogeneity of cholangiocytes make them unique compared with other epithelial cell types. Unfortunately, cholangiocytes are also targets of several human diseases including cholangiocarcinoma, PSC, PBC, and vanishing bileduct syndrome.
Hepatic stellate cells and portal fibroblasts HSCs and PFs are two cell types in the liver, whichare involved in the development of fibrosis. In normal healthy livers, HSCs are in a quiescent state and represent about 5–8% of the total number of liver cells. The function of quiescent HSCs in the liver is not well understood, but there is evidence showing that they play roles as an antigen-presenting cell type and in promoting natural killer cell proliferation. After liver damage, HSCs convert to an activated state characterized by proliferation, contractility, and chemotaxis. Once activated, HSCs begin to secrete collagen, leading to fibrosis and potentially cirrhosis of the liver. Some studies have shown that HSCs can begin to enter a senescent state upon activation and accumulate p53, thereby exacerbating the fibrotic reaction and reducing overall cell survival. Alternatively, some studies have demonstrated that senescent HSCs limit fibrosis by activating the immune response, causing interactions in natural killer cells. This effect can lead to resolution of the fibrotic response seen after acute liver injury. PFs are also involved in the fibrotic response of the liver and are classified as all fibroblasts in the portal region. First described by Carruthers et al., PFs are localized to the portal region, which differs from HSCs that are more distant and found in the perisinusoidal region of the liver. A linage tracing study by Asahina et al. provided evidence that HSCs and PFs originate from a common progenitor in early embryonic development. PFs have been differentiated from HSCs based on the expression of various markers, although these markers have not been sufficiently examined. Some studies have shown that PF-specific markers include fibulin-2, interleukin (IL)-6, elastin, and ecto-ATPase nucleoside triphosphate diphosphohydrolase-2 (NTPD2). Other markers that have been studied are P100, α2-macroglobulin, and neuronal proteins such as neuronal cell adhesion markers and synaptophysin (SYP). In cholangiopathies such as PBC, fibrosis begins in the peri-ductular region, which strongly implicates PFs as mediators of biliary fibrosis. PFs have cytoplasmic extensions that extend toward and come very close to the basolateral membrane of cholangiocytes. It has been reported that these dendrite-like extensions increase in number after injury of the liver. Following liver injury or when cultured on glass or plastic, PFs undergo myofibroblastic differentiation. This change causes PFs to produce large amounts of microfilament bundles containing α-SMA and arranged in line with the long axis of the cell.