Clarity and Challenges in Tissue Fibrosis

World journal of gastroenterology, 2016

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in ...

International Journal of Molecular Medicine, 2015

Liver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) in the hepatic parenchyma and represents an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. Hepatic stellate cells (HSCs) are the major cell type responsible for liver fibrosis. Following liver injury, HSCs become activated and transdifferentiate into myofibroblasts (MFBs) that lead to intrahepatic ECM accumulation. In the present study, we performed a meta-analysis of datasets which included whole-genome transcriptional data on HSCs in the quiescent and activated state from two different rodent species and identified commonly regulated genes. Several of the genes identified, including ECM components, metalloproteinases and growth factors, were found to be well-known markers for HSC activation. However, other significant genes also appeared to play important roles in hepatic fibrosis. The elucidation of the molecular events underlying HSC activation may be key to the identification of potential novel pharmacological targets for the prevention and treatment of liver fibrosis.

Pharmaceutics

The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human s...

Seminars in Liver Disease, 2015

Journal of Clinical Investigation, 2013

Cellular targets and multicellular fibrogenic units Activated myofibroblasts, representing a spectrum of similar ECM-producing cells that mainly derive from hepatic stellate cells and portal fibroblasts, are the major producers of the fibrotic ECM and the most downstream cellular effectors of liver fibrosis (Figure 1). Very few hepatic myofibroblasts in fibrosis stem from BM-derived fibrocytes (12). Moreover, complete epithelial-mesenchymal transition (EMT) of hepatocytes and bile duct epithelia to myofibroblasts may be a rare event-while an "incomplete" EMT of these cells with acquisition of a fibrogenic phenotype is common (28). Myofibroblasts and their products are primary targets for antifibrotic therapies, which in principle would address all types of fibrosis, including advanced fibrosis. Importantly, additional cellular elements that are either upstream of the myofibroblasts or tightly linked to fibrogenic activation within cellular units may provide a basis for complementary and more disease-specific antifibrotic approaches. A combination therapy approach may be more effective, given that crosstalk between different cell types generally underlies fibrogenic activation. Conceptually, three major multicellular functional units can be defined according to their constituent cell types: (a) perisinusoidal/vascular-pericytes, i.e., hepatic stellate Conflict of interest: The authors have declared that no conflict of interest exists.

Journal of Gastroenterology and Hepatology, 2008

The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes -formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) -the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrixproducing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts. Currently, the generation of matrix-synthesizing fibroblasts by epithelialmesenchymal transition, by influx of bone marrow-derived fibrocytes into damaged liver tissue, and by differentiation of circulating monocytes to fibroblasts after homing in the injured liver are discussed as important complementary mechanisms to enlarge the pool of (myo-)fibroblasts in the fibrosing liver. Among the molecular mediators, transforming growth factor-beta (TGF-b) plays a central role, which is controlled by the bonemorphogenetic protein (BMP)-7, an important antagonist of TGF-b action. The newly discovered pathways supplement the linear concept of HSC activation to myofibroblasts, point to fibrosis as a systemic response involving extrahepatic organs and reactions, add further evidence to a more or less uniform concept of organ fibrosis in general (e.g. liver, lung, kidney), and offer innovative approaches for the development of non-invasive biomarkers and antifibrotic trials.

2017

Liver fibrosis is highly prevalent in United States. No therapy has been successful to cure it so far. The current approaches in treatment are to prevent its causative etiology such as viral infection, alcohol abuse etc. or liver transplantation. Much progress has been made to understand the mechanisms for development of myofibroblasts in developing fibro genesis, inflammation and cell death. This review summarizes some of the key aspects of liver fibrosis and some novel therapies that have a potential to become a cure.

Biomedical and Pharmacology Journal, 2021

Liver fibrosis is considered: “a pathological repairing process in liver injuries leading to extracellular cell matrix (ECM) accumulation evidencing chronic liver diseases”. Chronic viral hepatitis, alcohol consumption, autoimmune diseases as well as non-alcoholic steatohepatitis are from the main causes of liver fibrosis (Lee et al., 2015; Mieli-Vergani et al., 2018). Hepatic stellate cells (HSCs) exist in the sinus space next to the hepatic epithelial cells as well as endothelial cells (Yin et al., 2013). Normally, HSCs are quiescent and mainly participate in fat storage and in the metabolism of vitamin A. HSCs are produced during liver injury and then transformed into myofibroblasts. The activated HSCs resulted in a sequence of events considered as marks fibrosis. The activation of HSCs mostly express alpha smooth muscle actin (α-SMA). Moreover, ECM is synthesized and secreted by HSCs that affects markedly the structure and function of the liver tissue leading to fibrosis (Tsuchi...

Cells

Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extr...

Gastroentérologie Clinique et Biologique, 2009

We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis and incipient cirrhosis. However, translation of this knowledge into clinical practice has been hampered by the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, as well as the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal. Furthermore, while cirrhosis and subsequent decompensation are accepted hard clinical end-points, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. This review focuses on basic mechanisms that underlay liver fibrosis progression and reversal and optimized strategies for preclinical antifibrotic drug development and validation. Therapies include several drugs that are of proven safety for other indications, agents that interfere with major fibrogenic or fibrolytic mechanisms, targeted drug delivery to the fibrogenic liver cells, and their potential combinations with hepatocyte or stem cell replenishment.