**3. Functional Interaction of Mast Cells and Other Cell Types Relevant for Fibrosis**

MCs have been realized as modulators of fibrotic processes in different organ systems. In line with a potential role of MCs in liver fibrosis is the finding that portal fibrosis is a frequent complication in SM. In this setting, MC numbers are highly increased in the liver [89,90]. It is a common feature that MC numbers increase in tissues during the process of fibrogenesis and the expansion of the MC pool in the liver is a common characteristic of liver fibrosis in humans and animal models due to damage by chemical toxins, viral infections, and cholestasis [91–94]. In fact, the physiological number of MCs in the liver is sparse and MC numbers strongly increase upon different pathological conditions [4,95–97]. According to Gentek et al., such an increase in MC numbers might occur via proliferation/differentiation of long-lived tissue-resident precursors [15].

The localization of MCs in the liver is mostly restricted to portal tracts and MCs are recruited to these areas under pathological conditions [98]. They are most likely absent from sinusoids and liver parenchyma [95,96]. However, in human liver, ≈10% of MCs have a perisinusoidal location [92]. Because of the prominent appearance in the portal tracts, most studies have been performed in the setting of cholangiopathies [99]. In those models, the inflammatory and fibrotic responses emanate from the portal fields based on a biliary reaction [82,83]. Due to this, the focus has been put on the interaction of MCs with cholangiocytes and to the pathways driving fibrogenic responses in HSCs/portal (myo)fibroblasts (see below). Nevertheless, there are a few reports addressing the crosstalk of MCs with other immune cells, i.e., Kupffer cells (see below) and the main cell type in the liver, i.e., the hepatocytes. For the latter, it was shown in vitro that syngenic BMMCs co-cultured with primary hepatocytes increases hepatocyte proliferation [100].

The infiltration (of myeloid lineage-derived cells from the bone marrow) and accumulation (differentiation of liver resident precursor cells, which can be differentiated in the presence of SCF) of MCs in the insulted liver has been shown in several studies and is unquestionable [101]. Even more, the isolation of MCs from liver of BDL-treated animals has been established [102]. It should be noted that not only the presence of MCs itself is of vital importance, but also the type of MCs within the liver (i.e., CTMCs or MMCs), when the functional interplay of cells is considered. General responses regulated by FcεRI or KIT are common to all MCs, whereas the contribution of effector enzymes for crosstalk with other cells varies in between different MC types [103]. A study in human liver tissue demonstrated that the amount of tryptase/chymase-positive MCs is higher than tryptase-positive cells in healthy and chronically diseased livers [104]. The cells isolated from BDL rats were chymase- and tryptase-positive, reflecting that these cells most likely represent CTMCs [102].
