3. Tenascin–C (TN-C)
According to the cellular structure of the liver, the perisinusoidal space (or space of Disse) is the location lies between the hepatic cords and sinusoids of the liver. It is commonly filled with various extracellular matrix (ECM) proteins whose function is to support the hepatic cords, regulate the proliferation and functions of hepatocytes and maintain the integrity of liver. CITATION Tan06 l 1033 (Tanaka, et al., 2006). When the liver is exposed to an acute injury, it can restore its original architecture in a relatively short period even when a large part of the organ is destroyed. On the other hand, chronic liver injury induces repetitive tissue damage, resulting in disabled regenerative capacity with inflammatory infiltrate and a chronic wound healing response. The response to chronic injury also includes necrosis and/or apoptosis of parenchymal cells and their replacement by extracellular matrix (ECM)CITATION Bat05 l 1033 (Bataller, 2005).
The tenascins are a highly conserved family of large oligomeric glycoproteins found in the extracellular matrix (ECM) of vertebrate organisms. The family contains four family members: tenascin-X, tenascin-R, tenascin-W, and tenascin-C.CITATION Bre09 l 1033 (Brellier, Tucker, & Chiquet-Ehrismann, 2009) CITATION Chi111 l 1033 (Chiquet-Ehrismann & Tucker, 2011). Tenascin-C (TN-C) is a hexameric multimodular ECM glycoprotein that is encoded by the TN-C gene in humans and is mostly expressed during embryonic development and tissue repair in adults and intensively induced by inflammation and cancer.CITATION Kas15 l 2057 (Kasprzycka, Hammarström, & Haraldsen, 2015) Tenascin-C has several molecular forms generated through alternative splicing and protein modifications. (Midwood & Orend, 2009) CITATION Mid16 l 1033 (Midwood, Chiquet, Tucker, & Orend, 2016).
3.1. Molecular structure of tenascin-C
Tenascin-C is an oligomeric extracellular matrix glycoprotein whose molecular weight is approximately 210–400 kDa and is composed of six subunits. The size of tenascin-C subunit varies as a result of an alternative splicing of the fibronectin repeats at the pre-mRNA level. Each subunit contains a Tenascin assembly (TA) domain that forms a coiled-coil at the N-terminus, epidermal growth factor (EGF)-like repeats, fibronectin type III – like (FNIII) repeats, and a fibrinogen-like domain. CITATION Tan06 l 1033 (Tanaka, et al., 2006). Each of these domains interacts with different binding partners, including cell surface receptors and other extracellular components, CITATION Ore05 l 1033 (Orend, 2005). The FNIII repeats contain a region undergoes alternative splicing, which generates various forms with different molecular weights. A small molecular weight variant of TN-C formed after splicing exists constitutively in normal tissues, whereas the large molecular weight variants, including different combinations of alternative spliced FNIII repeats, are particularly expressed in tissues suffering pathological situations CITATION Ghe01 l 1033 (Ghert, et al., 2001) CITATION Has04 l 1033 (Hasegawa, et al., 2004) CITATION Tan06 l 1033 (Tanaka, et al., 2006)
Fig.1 Multidomain structure of human tenascin-C (TN-C) subunit. The amino-termini of six TN-C subunits are united to construct a hexamer. Each subunit consists of 14+1/2 epidermal growth factor-like domains, 8–15 fibronectin type III (FNIII) domains, depending on alternative RNA splicing, and a single fibrinogen-like domain. The universal FNIII domains (FNIII repeats 1–5 and FNIII repeats 6–8) are present in all TN-C variants. CITATION ElK07 l 2057 (El-Karef, et al., 2007)3.2. Role of tenascin-C in liver injury
Obviously, inflammation is the immediate and serious response to tissue injury and infection. Tenascin-C is induced and expressed at sites of inflammation regardless of the location or type of causative agent. In case of liver injury, TN-C is upregulated and accumulated at parenchymal-connective tissue interfaces and in perisinusoidal spaces and its expression is concentrated in areas of increased immune cell infiltration. In addition, TN-C promotes activation of T lymphocytes that secrete inflammatory cytokines including IFN-?, TNF-?, and IL-4, which in turn activate quiescent hepatic stellate cells (HSCs) that differentiate into myofibroblasts and secrete large amounts of extracellular matrix proteins especially type I collagen (Col I) CITATION Tro12 l 2057 (Troeger, et al., 2012) CITATION Dep15 l 2057 (Depito & Schwabe, 2015).
Generally, all tenascins have the capacity to alter cell adhesion directly or via an interaction with fibronectin and cell-tenascin interactions lead to increased cell motility. For TN-C, there is a correlation between its elevated expression and increased cell metastasis as it retards cell attachment and dispersion on ECM proteins (eg: fibronectin and laminin) and stimulates cell tethering and rolling. CITATION Cla97 l 2057 (Clark, Erickson, & Springer, 1997) CITATION Brö13 l 2057 (Brösicke, van Landeghem, Scheffler, & Faissner, 2013). Previous studies conducted on mice suffering concanavalin A-induced hepatic fibrosis revealed that mice lacking TN-C exhibited reduced inflammatory cell and myofibroblast infiltration with a sharp decline in inflammatory cytokine expression. Moreover, transforming growth factor-? (TGF)-? mRNA was upregulated in wild type mice and was significantly higher than its level in TN-C null mice. CITATION ElK07 l 2057 (El-Karef, et al., 2007). Consequently, it was potentially suggested that there is a contribution between TN-C and progression of liver fibrogenesis.
Observations on previous studies on mice:
1. Gradual increase in TNC deposition in WT mice compared with TNKO mice.
2. TNC mRNA levels increase sequentially and peaked after the 9th injection in WT mice.
3. Collagen deposition was less intense in TNKO than WT mice.
4. Procollagen I and III transcripts were significantly upregulated in WT compared with TNKO mice.
5. Inflammatory infiltrates were most prominent after the 3rd-6th injections in both groups and were less intense in TNKO than WT mice.
6. Interferon gamma, tumor necrosis factor alpha and interleukin-4 mRNA levels were significantly higher in WT than TNKO mice.
7. Activated hepatic stellate cells (HSCs) and myofibroblasts (cellular source of TNC and procollagens) were more common in WT livers.
8. Transforming growth factor-beta (TGF-?1) mRNA expression was significantly up regulated in WT type but not in TNKO mice.