What Is a Hepatic Stellate Cell?

Liver stellate cells account for 15% of the total number of liver intrinsic cells and about 30% of non-parenchymal cells. HSC exists in the Disse cavity, which is fusiform or polygonal. There are multiple lipid droplets rich in vitamin A in the cytoplasm. Its elongated protrusions extend outwards around the sinusoidal endothelial cells. It is derived from the storage of retinal The primary part of things. In normal liver, stellate cells are at rest, do not express alpha smooth muscle actin (-SMA), have low proliferative activity, and have low ability to synthesize collagen. Their main function is to store retinals.

Chinese name: Hepatic stellate cells

Foreign name: hepatic stellate cell, HSC
Department: Hepatobiliary surgery

Hepatic stellate cells

Hepatic stellate cells are the main source of ECM. HSCs are activated and transformed into myofibroblast-like cells (MFC). HSCs are the ultimate target cells for various fibrotic factors. Hepatic stellate cells activate and transform into myofibroblast-like cells (MFC).

Fibrotic factors all take HSC as the ultimate target cell, and under normal circumstances, hepatic stellate cells are at rest. When the liver is damaged by inflammation or mechanical stimulation, hepatic stellate cells are activated, and their phenotype changes from resting to activated. Activated hepatic stellate cells participate in the formation of liver fibrosis and the reconstruction of intrahepatic structures through proliferation and secretion of extracellular matrix, and on the other hand, increase the intrahepatic sinusoidal pressure through cell contraction.

Liver stellate cells background

As early as 1876, when Carlvon Kupffer in Germany used the gold chloride staining method to study the liver's nervous system, he unintentionally found stellate cells around the hepatic sinusoids and named them sternzellen. In 1898, when Kupffer stained rabbit liver with Indian ink, hepatic macrophages that could swallow ink particles were observed, which was later named Ku in honor of Kupffer

Carl von Kupffer pffer cells. Because it is also stellate, Kupffer mistakenly confuses liver macrophages with stellate cells, thinking that stellate cells are liver macrophages. This view was widely recognized at the time. Until 1951, a Japanese scholar Toshio Ito discovered a type of cells rich in lipid droplets and surrounded by reticular fibers around a human liver sinus through a light microscope, and named it ItoCel1s or fat storage cells. (Fat-storingcells). In 1958, Suzuki observed this star-shaped cell in the Disse cavity with silver staining, and found that the process was connected to the autonomic nerve endings in the liver. He believed that these cells could transmit impulse from the autonomic nerves in the liver. Give liver parenchymal cells and call them "interstitial cells"; in 1966, Bronfenmajor confirmed the discovery of Ito cells, and renamed the cells as adipocytes; in 1971, KenjiroWake used an electron microscope to combine Gold chloride staining and Sudan red staining revealed that the Ito cells described by Ito and the stellate cells found by Kupffer were originally the same type of cells, and pointed out that the above cells were different from sinusoidal endothelial cells and were not intrahepatic. Macrophages. These cells are rich in VitaminA and lipid droplets, in which autofluorescence from lipid droplets and the ability of such cells to be stained with gold chloride are related to the presence of VitaminA. So far, people have revealed the true face of this star-shaped cell, and started to study its function, and gradually discovered its relationship with liver fibrosis. In 1995, it was officially named HSC internationally.

Nature and function of hepatic stellate cells

HSC is located in the Disse space, next to sinusoidal endothelial cells (SEC) and liver cells. Its morphology is irregular, and the cell body is round or irregular, and several stellate cell processes often extend around the hepatic sinus. In addition, HSC also extended the cell process to make contact with hepatocytes and adjacent stellate cells. The cytoplasm of HSC contains 1 to 14 lipid droplets rich in vitamin A and triglyceride with a diameter of about 1.0 to 2.0 m. The cytoplasm is rich in free ribosomes, rough endoplasmic reticulum, and a developed Golgi complex. The nucleus is irregular in shape. Due to the squeeze of lipid droplets, the nucleus often has one or more depressions. One or two nucleoli can be seen in the nucleus. The number of HSCs in the normal liver is very small, accounting for only 5% to 8% of the total number of hepatocytes and 1.4% of the total volume.

Under normal circumstances, HSC appears as a stationary type rich in VitA lipid droplets, and its functions are mainly:

(1) Metabolism and storage VitA: The liver stores about 80% of vitamin A in the body, which plays an important role in the metabolism of vitamin A in the body. After being re-esterified in the small intestine, retinal is transported to the liver and bound to specific retinal-binding proteins, and then transported to nearby HSC storage.

(2) Storage fat: Fat droplets in the cytoplasm of normal HSCs contain a large amount of triglycerides, which provide energy for liver cells.

(3) Synthesis and secretion of collagen and glycoproteins

Hepatic stellate cells Matrix components such as sugar: Studies have shown that HSC is the main synthetic cell of extracellular matrix (ECM) in normal and fibrotic liver. The collagen synthesized by HSC in normal liver is mainly type , and , and its synthesis amount is 10 times that of hepatocytes and 20 times that of endothelial cells. HSC can also synthesize glycoprotein components such as fibronectin, laminin, and crude fibrin, as well as proteoglycans such as dermatan sulfate, chondroitin sulfate, and hyaluronic acid.

(4) Synthesis of matrix metalloproteinase (MMP) and tissue inhibitors (tissueinhibitor of metalloproteinases, TIMP): Under normal circumstances, HSC can secrete a variety of collagenases and matrix degradation proteases such as matrix metalloproteinase (MMP) -1, MMP-2 degrades various extracellular matrices, and secretes tissue inhibitor of metalloproteinase (TIMP-1) to prevent excessive degradation of collagen, so that liver ECM synthesis and decomposition are in a dynamic equilibrium.

(5) Expression of cytokines and receptors: Under normal circumstances, HSC can secrete hepatocyte growth factor (HGF) and participate in the regulation of liver cell regeneration. In addition, HSC can also express a small amount of transforming growth factor (TGF-, TGF-), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF), while HSC can express TGF-1 II -subunits of type III receptors and PDGF receptors.

(6) Participate in the regulation of hepatic sinus blood flow: HSC stretches out the cell process to surround the hepatic sinus, and regulates the microcirculation in the hepatic sinus through the contractile function of its elongated process, which affects the blood flow distribution of the liver and portal pressure.

Biological characteristics of hepatic stellate cells

Under normal circumstances, hepatic stellate cells are at rest. When the liver is damaged by inflammation or mechanical stimulation, hepatic stellate cells are activated, and their phenotype changes from resting to activated. Hepatic stellate cells are located in the Disse cavity around the liver sinus, accounting for approximately 13% of all liver cells. In normal HE stained liver tissue sections, stellate cells cannot be displayed, but they can be localized by immunohistochemistry and can be isolated for in vitro cell culture. Under normal circumstances, hepatic stellate cells are at rest. Its physiological functions in the liver are mainly involved in the metabolism of vitamin A and the function of storing fat. The cytoplasm of hepatic stellate cells contains lipid droplets of retinoids. The main storage of vitamin A, liver star

Hepatic stellate cells The stellate cells also regulate blood flow in the blood vessels and sinusoids. Under pathological conditions, such as when the liver is stimulated by physical, chemical, and viral infection biological factors, hepatic stellate cells proliferate and activate, transform into "myofibroblasts", express -smooth actin, and synthesize ECM. When the liver has inflammation, hepatic stellate cells are activated. Gressner et al. Proposed a "three-step cascade" of hepatic stellate cell activation. Mode-activated hepatic stellate cells have the following characteristics:

1. Cell body enlarges and cell process stretches. Lipid droplets disappeared in the cytoplasm, and VitA content decreased. The cytoplasm has a rough inner mesh and a Golgi apparatus, which has strong protein synthesis capabilities;

2. Increased cell proliferation frequency and migration to liver injury sites;

3. Express -smooth muscle actin (-SMA), vimentin and desmin, and become myofibroblasts;

4. Enhanced contractility;

5. Increased ECM secretion;

6. Increased secretion of cytokines, chemokines and receptors;

7. Increased TIMP synthesis and secretion reduces degradation of ECM components. The expression of -SMA is a sign of HSC activation.

Hepatic stellate cell activation

The continuous activation of hepatic stellate cells is a key link in the development of liver fibrosis. Activated hepatic stellate cells participate in the formation of liver fibrosis and the reconstruction of intrahepatic structures through proliferation and secretion of extracellular matrix, and on the other hand, the intrahepatic sinusoidal pressure increases through cell contraction. These two types of changes ultimately lay the liver The pathological basis of fibrosis and portal hypertension. Hepatic stellate cells

Activated hepatic stellate cells The process is very complex and consists of two main phases: the start-up phase and the continuous phase. The sustained phase is that these stimuli maintain the activated phenotype of hepatic stellate cells, which results in the formation of liver fibrosis. The initiation phase is mainly dependent on paracrine stimuli. The sustained phase is related to both paracrine and autocrine stimuli.

Hepatic stellate cell initiation stage

The initiation stage refers to changes in early gene expression and changes in cell phenotypes produced by stimuli such as cytokines. When liver parenchymal cells are damaged, adjacent liver cells, Kupffer cells, sinus endothelial cells, and platelets can secrete a variety of cytokines, such as tumor necrosis factor (TNF-) and transforming growth factor through paracrine effects. (TGF-), insulin growth factor (IGF-1), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), endothelin (ET) -1, etc., act on HSC and cause myogenesis Fibroblast (myofibroblast, MFB) -like phenotype transformation, activation and lead to cell proliferation, increased ECM synthesis, etc. Activated hepatic stellate cells can auto-secret cytokines such as TGF, PDGF, and ET to enable activation. At this time, fibrosis will continue even if the primary factors are removed.

Hepatic stellate cells

Sustained stage refers to maintaining the activated state of stellate cells and the formation of fibers due to the effects of the various factors mentioned above. Hepatic stellate cell activation has the following characteristic changes in the sustained phase. The direct or indirect effects of these changes are increased ECM deposition. The activation of hepatic stellate cells at this stage is regulated by both autocrine and paracrine.

(1) Cell proliferation: PDGF is the strongest mitogen of hepatic stellate cells. PDGF receptors in the early stages of hepatic stellate cell activation enhance the response of hepatic stellate cells to this mitogen;

(2) Chemotactic aggregation of cells: Hepatic stellate cells can move to the site of chemical chemotaxis, which explains to some extent why hepatic stellate cells are distributed in the inflammatory space in the liver;

(3) Fibrosis: Increasing stroma formation is the most direct way for liver fibrosis due to hepatic stellate cell activation. On the one hand, the amount of ECM synthesis increases; on the other hand, the types of synthetic ECM are abnormal. Under normal circumstances, hepatic stellate cells are dominated by synthetic collagen.

Hepatic stellate cells . After activation, it mainly produces collagen;

(4) Cell contraction effect: The contraction effect of hepatic stellate cells may be an important factor that causes portal vein resistance to increase after liver fibrosis. The fibrous bands typical of advanced liver cirrhosis are filled with a large number of hepatic stellate cells. Activated hepatic stellate cells obstruct portal blood flow by contracting the perisinus and contracting the sclerotic liver. The main stimulating factor that causes contraction of hepatic stellate cells is endothelin-1 (ET-1), and its receptor is expressed in resting or activated HSCs;

(5) Matrix degradation: During liver fibrosis, along with ECM remodeling, changes in matrix protease quality and quantity play an important role. Hepatic stellate cells can express almost all the key components required for matrix degradation. Therefore, activated hepatic stellate cells not only play a role in the process of ECM generation, but also play an important role in the process of ECM degradation. The matrix protease family is a class of calcium-dependent proteases that specifically degrade collagen and some non-collagen components. According to the substrate specificity of matrix proteases, they are classified into five categories: interstitial collagenase; gelatinase; stromelysin; membrane-type matrix metalloproteinase; metal elastase;

(6) Retinol disappears: With the activation of hepatic stellate cells, the cells lose their characteristic nuclear retinol (vitamin A) lipid droplets;

(7) Leukocyte chemotaxis and release of cytokines: In addition to a variety of cytokines in the liver acting through paracrine, cytokines autocrine from hepatic stellate cells are also important for their long-lasting activation. Activated hepatic stellate cells secrete TGF-B and ET-1. Lead to hepatic stellate cells to produce a large number of ECM and contractility. Hepatic stellate cells can also expand inflammatory effects by inducing monocyte macrophage infiltration.

Hepatic stellate cell apoptosis

Activated hepatic stellate cells have two destinations:

(1) Transition from active state to stationary state. Studies have suggested that IL-10 is a stimulating factor that can regulate this response, which can down-regulate the inflammatory response and increase collagenase activity in the interstitial space;

(2) Apoptosis and death. In vitro culture experiments show that the hepatic stellate cells do not undergo apoptosis, and the hepatic stellate cells undergo spontaneous apoptosis while being activated. In recent years, research on the molecular mechanism of hepatic stellate cell apoptosis has progressed rapidly, and it has been proved that a variety of gene products are involved in the process of hepatic stellate cell apoptosis. These include death receptor families such as the Fas and FasL systems, aspartic acid

Hepatic stellate cells The heterocysteine proteases are the Caspase family and the bcl-2 regulatory protein family. Through in-depth research on the biochemical characteristics, biological functions, and molecular mechanisms of upstream and downstream molecules of these protein family members, two main signal transduction pathways of hepatic stellate cell apoptosis have been proposed: the mitochondrial-dependent pathway of apoptosis and the death Body approach. As a result of both pathways, a cascade of the Caspase family is triggered, which ultimately manifests itself as apoptosis.

Hepatic stellate cell regulation

1. Fas / FasL system Fas, also called Apo-1 or CD95, belongs to the tumor necrosis factor (TNF) receptor and nerve growth factor (nervegrowthfactor (NGF) receptor superfamily). Fas is a 48kDa type I transmembrane protein molecule consisting of 319 amino acids and located on the long arm of human chromosome 10. Fas is mainly distributed in tissue cells, and a small amount is in soluble form (sF

Regulation of hepatic stellate cells as) is present in the cytoplasm and serum. Fas Ligand (FasLigand, FasL) is a type II transmembrane protein molecule with a molecular weight of about 40 kDa and belonging to the TNF family. It is mainly expressed on the surface of activated T lymphocytes. The binding of FasL or Fas antibody to Fas on the cell surface can induce apoptosis.

2. In recent years, the Caspases family has found a variety of cysteineaspartate-specific proteinase (caspase) family members in the body. They are homologous proteases with similar structural characteristics. These proteases are specific in the substrate. Peptide bonds are cleaved after the aspartic acid sequence. At least thirteen species were found in mammalian cells, numbered Caspase-1 to 13, including two mouse Caspase-11, 12 whose corresponding counterparts have not been found in humans. They can be divided into three subfamilies based on their sequence homology: ICE-like, ICH-1-like, and CPP32-like proteases. Overexpression of the Caspase family can cause a series of irreversible protein cleavages and eventually lead to cell death. It can be said that the expression of Caspases protein is the last pathway common to various apoptotic mechanisms.