Hepatic Stellate Cell: A Double-Edged Sword in the Liver

Hepatic stellate cells (HSCs) are located in the space of Disse, between liver sinusoidal endothelia cells (LSECs) and hepatocytes. They have surprised and excited hepatologists for their biological characteristics. Under physiological quiescent conditions, HSCs are the major vitamin A-storing cells of the liver, playing crucial roles in the liver development, regeneration, and tissue homeostasis. Upon injury-induced activation, HSCs convert to a pro-fibrotic state, producing the excessive extracellular matrix (ECM) and promoting angiogenesis in the liver fibrogenesis. Activated HSCs significantly contribute to liver fibrosis progression and inactivated HSCs are key to liver fibrosis regression. In this review, we summarize the comprehensive understanding of HSCs features, including their roles in normal liver and liver fibrosis in hopes of advancing the development of emerging diagnosis and treatment for hepatic fibrosis.

Hepatic stellate cells: current state and open questions

This review article summarizes 20 years of our research on hepatic stellate cells within the framework of two collaborative research centers CRC575 and CRC974 at the Heinrich Heine University. Over this period, stellate cells were identified for the first time as mesenchymal stem cells of the liver, and important functions of these cells in the context of liver regeneration were discovered. Furthermore, it was determined that the space of Disse – bounded by the sinusoidal endothelium and hepatocytes – functions as a stem cell niche for stellate cells. Essential elements of this niche that control the maintenance of hepatic stellate cells have been identified alongside their impairment with age. This article aims to highlight previous studies on stellate cells and critically examine and identify open questions and future research directions.

Descriptive Histopathological and Ultrastructural Study of Hepatocellular Alterations Induced by Aflatoxin B1 in Rats

Liver sinusoids are lined by fenestrated endothelial cells surrounded by perisinusoidal cells, Kupffer cells, and pit cells, as well as large granular lymphocytes. The functional ability of the liver cells can be substantially modified by exposure to toxins. In the current work, we assessed the histopathological and ultrastructural effects of a time-course exposure to aflatoxin B1 (AFB1) on the hepatic structures of rats. A total of 30 adult female Wistar rats were randomly divided into three groups: a control group, a group orally administered 250 µg/kg body weight/day of AFB1 for 5 days/week over 4 weeks, and a group that received the same AFB1 treatment but over 8 weeks. Histopathological and ultrastructural examinations of hepatocytes revealed massive vacuolar degeneration and signs of necrosis. Furthermore, the rat liver of the treated group exhibited damage to the sinusoidal endothelium, invasion of the space of Disse with hyperactive Kupffer cells, and some immune cells, as well as Ito cells overloaded with lipids. In addition, damaged telocytes were observed. Taken together, our results indicate that AFB1 induces irreversible adverse effects on the livers of rats.

The Space of Disse: The Liver Hub in Health and Disease

Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.

Post-developmental extracellular proteoglycan maintenance in attractin-deficient mice

Objective: Neurodegeneration and hair pigmentation alterations in mice occur consequent to aberrations at the Atrn locus coding for the transmembrane form of attractin. Earlier results pointed to a possible involvement in intracellular trafficking/export of secretory vesicles containing proteoglycan. Here we examined kidney and liver, both heavily dependent upon proteoglycan, of attractin-deficient mice to determine whether abnormalities were observed in these tissues.Results: Histological and histochemical analysis to detect glycosylated protein identified a severe loss in attractin-deficient mice of extracellular proteoglycan between kidney tubules in addition to a loss of glycosylated material within the intratubular brush border. In the liver, extracellular matrix material was significantly depleted between hepatocytes together with swollen sinuses and aberrations in the proteoglycan-dependent space of Disse. These results are consistent with a generalized defect in extracellular proteoglycan deposition in Atrn -mutant mice and support previous reports suggesting a role for attractin in the secretory vesicle pathway.

Space of Disse: a stem cell niche in the liver

Recent evidence indicates that the plasticity of preexisting hepatocytes and bile duct cells is responsible for the appearance of intermediate progenitor cells capable of restoring liver mass after injury without the need of a stem cell compartment. However, mesenchymal stem cells (MSCs) exist in all organs and are associated with blood vessels which represent their perivascular stem cell niche. MSCs are multipotent and can differentiate into several cell types and are known to support regenerative processes by the release of immunomodulatory and trophic factors. In the liver, the space of Disse constitutes a stem cell niche that harbors stellate cells as liver resident MSCs. This perivascular niche is created by extracellular matrix proteins, sinusoidal endothelial cells, liver parenchymal cells and sympathetic nerve endings and establishes a microenvironment that is suitable to maintain stellate cells and to control their fate. The stem cell niche integrity is important for the behavior of stellate cells in the normal, regenerative, aged and diseased liver. The niche character of the space of Disse may further explain why the liver can become an organ of extra-medullar hematopoiesis and why this organ is frequently prone to tumor metastasis.

Chronic Organic Arsenic Induced Liver Ultra Structural Damage

Introduction: Inorganic arsenic is one of the environmental toxins that has been associated with increased risk of cardiovascular diseases and vascular contributions to liver diseases. It has generally been thought to be more toxic than organic arsenic. In human liver, inorganic arsenic promotes vascular remodelling, portal fibrosis and hypertension. The purpose of the current study was to determine whether chronic exposure to organic arsenic impair liver ultrastructure as in inorganic arsenic exposure. Materials and Methods: Twenty eight male SpragueDawley rats were divided into 2 groups with their own control group. They received oral intubation of monosodium- methylarsonate (MSMA) at 63.30 mg/kg body weight for 4 and 6 months duration respectively while the control groups received distilled water. The liver of euthanized rats were perfused- fixed with glutaraldehyde for transmission electron microscopy processing. Results: TEM revealed a marked reduction in the number of mitochondria in both treatment groups. Some typical features of apoptosis are present with pyknotic nuclei of hepatocytes and disintegrated hepatic cytoplasm in 4- month groups. The microvilli of hepatocyte are almost completely absent with the presence of many fibre bundles (collagen fibres) widening the space of Disse. In 6-month treatment group, disintegrated cytoplasms are more prominent with degrading mitochondria of varying stages. Liver sinusoidal endothelial cells (LSEC) of 6-month treatment group are noted to have chromatin condensation with few caveolae seen. Conclusion: Chronic exposure of MSMA leads to necrotic changes of hepatocytes and apoptotic changes in LSEC and collagenisation in the space of Disse.

Histological insight into the hepatic tissue of the Nile monitor (Varanus niloticus)

The liver of reptiles is considered an important study model for the interaction between environment and hepatic tissue. Little is known about the histology of the liver of reptiles. The aim of the current study was to elucidate the histological architecture of the liver of the Nile monitor (Varanus niloticus). Liver fragments from the Nile monitor were collected in the summer season and processed for the light and electron microscopy. The liver of the Nile monitor was bi-lobed and the right lobe was found to be larger than the left lobe. Histological examination revealed indistinct lobulation of the liver, and the central vein, sinusoids and portal area were haphazardly organized. The hepatic parenchyma consisted of hepatocytes arranged in glandular-like alveoli or tubules separated by a network of twisted capillary sinusoids. The hepatocytes were polyhedral in shape with vacuolated cytoplasm and the nucleus was single rounded, eccentric, large and vesicular with a distinct nucleolus. The hepatocytes contained numerous lipid droplets, abundant glycogen granules and well-developed RER and mitochondria. The hepatocytes appeared to secrete into the bile canaliculi through the disintegration of their dark cytoplasm into the bile canaliculi. The space of Disse separating between the hepatocytes and sinusoids contained many recesses. The portal area contained branches of the portal vein, hepatic artery, bile duct and lymphatic vessels embedded in a connective tissue. Some non-parenchymal cells were described such as Kupffer cells, heterophils, melano-macrophages, intercalated cells, myofibroblasts in addition to the endothelium of the sinusoids. This is the first report about the histological structure of the liver of the Egyptian Nile monitor. The result presented here should be considered a baseline knowledge to compare with the pathological affections of the liver in this species.