Embryonic Liver Fodrin Involved In Stellate Cell Activation And Formation Of Regenerative Nodule In Liver Cirrhosis

IntroductionLiver fibrosis or cirrhosis, the ultimate pathological consequence of severe chronic liver damage, represents a major medical problem with significant morbidity and mortality worldwide.Liver cirrhosis is characterized by deposition of extracellular matrix (ECM), the distortion of the liver parenchyma replaced by regenerative nodules and altered blood flow.In normal liver, ECM is a highly dynamic substratum with a precisely regulated balance between synthesis and degradation. During chronic liver injury, however,ECM production exceeds its degradation, and hepatic fibrosis develops as a result of the progressive thickening of fibrotic septae and chemical cross-linking of collagen. Moreover, these changes in ECM composition directly stimulate fibrogenesis Underlying this response is the activation of resident mesenchymal cells into contractile MF, primarily derived from HSCs, that generate scar, which encapsulates injury. HSCs are a resident mesenchymal cell type located in the subendothelial space of Disse, interposed between sinusoidal endothelium and hepatocytes. Following liver injury, HSCs become activated, which leads to the conversion of a resting vitamin A-rich cell [a quiescent HSC (qHSC)] to one that has lost vitamin A droplets, leading to increased proliferation and contraction and the release of proinflammatory, profibrogenic, and promitogenic cytokines. These activated cells are capable of enhanced migration and deposition of ECM components. HSC activation can be conceptually divided into two phases:initiation and erpetuation. Initiation, also known as the preinflammatory stage, refers to early changes in gene expression and phenotype. It is the result of primarily paracrine stimulation from damaged parenchymal cells. Maintenance of these stimuli leads to a perpetuation phase regulated by autocrine and paracrine stimuli. Perpetuation involves at least six distinct changes in HSC behavior, including proliferation, chemotaxis, fibrogenesis, contractility, matrix degradation, and retinoid loss (23).Following liver injury, several cell types can secrete inflammatory cytokines; these cell types include KCs, hepatocytes, HSCs, natural killer (NK) cells, lymphocytes, and dendritic cells. Cytokines are a family of proteins that include chemokines [monocyte chemotactic protein 1 (MCP-1), RANTES, IL-8], interferons (IFN-a, IFN-y), interleukins (IL-1, IL-6, IL-10), growth factors, adipokines, Of cytokines involved in liver fibrogenesis, TGF-₁ is the most potent profibrogenic mediator [10,12-15].TGF-β1 transforms HSCs into myofibroblasts, which results in up-regulation of many ECM proteins and down-regulation of their degradation by matrix metalloproteinases and tissue inhibitor of metalloproteinases. Blockade of the TGF-β1 signal by dominant negative typeâ…¡TGF receptor suppressed the development of dimethylnitrosamine-induced hepatic fibrosis [16,17]. ELF, aβ-spectrin, has been demonstrated to play a pivotal role in TGF-βsignalling [7,8]. It is involved in TGF-β/Smad signalling pathway as an adaptor [7,8] Previous studies had demonstrated the function of ELF during development and tumorigenesis. As showed in elf-/- mice brain,expression of cdk4 was increased and cell in brain was resistant to apoptosis. Loss of ELF in the liver leads the cancer formation by deregulated hepatocyte proliferation and stimulation of angiogenesis in early cancers.Study in lung cancer revealed that disruption in TGF-βsignaling mediated by loss of ELF leads to cell-cycle deregulation by modulating CDK4 and ELF highlights a key role of TGF-βadaptor protein in suppressing early lung cancer.In view of the importance of TGF-βsignal in liver fibrosis, we hypothesize that ELF, an adaptor in TGF-βsignalling pathway may play a key role in liver cirrhosis. Therefore, we examined ELF expression in cirrhotic liver and evaluated the role of ELF in liver cirrhosis. In this study, we demonstrate that ELF is required for HSC activation and ECM deposition in activated HSCs cultured in vitro; in addition, interestingly, ELF down-regulation in regenerative hepatocytes is involved in the formation of regenerative nodules derived from hepatic progenitor cells (HPC). Thus, this study has identified, for the first time, a molecule participates in liver cirrhosis through the involvement of HSC activation and the formation of regenerative nodule.