home Diseases Stellate cells. Liver fibrosis: past, present and future Portal triad and acinus

Stellate cells. Liver fibrosis: past, present and future Portal triad and acinus

Sinusoidal cells (endothelial cells, Kupffer cells, stellate and pit cells) together with the area of hepatocytes facing the lumen of the sinusoid form a functional and histological unit.

Endothelial cells line the sinusoids and contain fenestrae, forming a stepped barrier between the sinusoid and the space of Disse. Kupffer cells are attached to the endothelium.

Stellate cells livers are located in the space of Disse between hepatocytes and endothelial cells. Disse space contains tissue fluid that flows further into the lymphatic vessels of the portal zones. With an increase in sinusoidal pressure, the production of lymph in the space of Disse increases, which plays a role in the formation of ascites when the venous outflow from the liver is impaired.

The Kupffer cell contains specific membrane receptors for ligands, including the Fc fragment of immunoglobulin and complement component C3b, which play an important role in antigen presentation.

Kupffer cells are activated during generalized infections or trauma. They specifically absorb endotoxin and in response produce a number of factors, such as tumor necrosis factor, interleukins, collagenase and lysosomal hydrolases. These factors increase the feeling of discomfort and malaise. The toxic effect of endotoxin is thus due to the secretion products of Kupffer cells, since it itself is non-toxic.

The Kupffer cell also secretes metabolites of arachidonic acid, including prostaglandins.

The Kupffer cell has specific membrane receptors for insulin, glucagon and lipoproteins. The carbohydrate receptor for N-acetylglycosamine, mannose and galactose may mediate the pinocytosis of some glycoproteins, especially lysosomal hydrolases. In addition, it mediates the uptake of immune complexes containing IgM.

In the fetal liver, Kupffer cells perform erythroblastoid function. Recognition and rate of endocytosis by Kupffer cells depend on otopsonins, plasma fibronectin, immunoglobulins and tuftsin, a natural immunomodulatory peptide. These “liver sieves” filter macromolecules of various sizes. Large, triglyceride-rich chylomicrons do not pass through them, and smaller, triglyceride-poor, but cholesterol- and retinol-rich residues can penetrate into the space of Disse. Endothelial cells vary somewhat depending on their location in the lobule. Scanning electron microscopy shows that the number of fenestrae can be significantly reduced with the formation of a basement membrane; These changes are especially pronounced in zone 3 in patients with alcoholism.

Sinusoidal endothelial cells actively remove macromolecules and small particles from the circulation via receptor-mediated endocytosis. They carry surface receptors for hyaluronic acid (the main polysaccharide component of connective tissue), chondroitin sulfate and a glycoprotein containing mannose at the end, as well as type II and III receptors for FcIgG fragments and a receptor for lipopolysaccharide binding protein. Endothelial cells perform a cleansing function, removing enzymes that damage tissue and pathogenic factors (including microorganisms). In addition, they cleanse the blood of destroyed collagen and bind and absorb lipoproteins.

Liver stellate cells(fat-storing cells, lipocytes, Ito cells). These cells are located in the subendothelial space of Disse. They contain long extensions of cytoplasm, some of which are in close contact with parenchymal cells, and others reach several sinusoids, where they may participate in the regulation of blood flow and thus influence portal hypertension. In a normal liver, these cells are the main storage site for retinoids; morphologically this manifests itself as fat droplets in the cytoplasm. After releasing these droplets, the stellate cells become similar to fibroblasts. They contain actin and myosin and contract when exposed to endothelin-1 and substance P. When hepatocytes are damaged, stellate cells lose fat droplets, proliferate, migrate to zone 3, acquire a phenotype resembling that of myofibroblasts, and produce collagen types I, III and IV, and also laminin. In addition, they secrete cell matrix proteinases and their inhibitors, such as tissue inhibitor of metalloproteinases (see Chapter 19). Collagenization of the space of Disse leads to a decrease in the entry of protein-bound substrates into the hepatocyte.

Pit cells. These are very mobile lymphocytes - natural killer cells, attached to the endothelial surface facing the lumen of the sinusoid. Their microvilli or pseudopodia penetrate the endothelial lining, connecting with the microvilli of parenchymal cells in the space of Disse. These cells do not live long and are renewed by circulating lymphocytes that differentiate in the sinusoids. They contain characteristic granules and vesicles with rods in the center. Pit cells have spontaneous cytotoxicity towards tumor and virus-infected hepatocytes.

Sinusoidal Cell Interactions

A complex interaction occurs between Kupffer cells and endothelial cells, as well as between sinusoid cells and hepatocytes. Activation of Kupferalipopolysaccharides inhibits the uptake of hyaluronic acid by endothelial cells. This effect is possibly mediated by leukotrienes. Cytokines produced by sinusoid cells can both stimulate and suppress the proliferation of hepatocytes.

Above, a schematic representation of an Itoh cell (HSC) adjacent to nearby hepatocytes (PCs), below hepatic sinusoidal epithelial cells (ECs). S - liver sinusoid; KC - Kupffer cell. Bottom left - Ito cells in culture under a light microscope. Bottom right - Electron microscopy reveals numerous fat vacuoles (L) of Itoh cells (HSCs) that store retinoids.

Ito cells(synonyms: liver stellate cell, fat storage cell, lipocyte, English Hepatic Stellate Cell, HSC, Cell of Ito, Ito cell) - pericytes contained in, capable of functioning in two different states - calm And activated. Activated Ito cells play a major role in the formation of scar tissue in liver damage.

In an intact liver, stellate cells are found in calm state. In this state, the cells have several projections covering a sinusoidal capillary. Another distinctive feature of cells is the presence of vitamin A (retinoid) reserves in their cytoplasm in the form of fat droplets. Quiet Ito cells make up 5-8% of all liver cells.

Ito cell outgrowths are divided into two types: perisinusoidal(subendothelial) and interhepatocellular. The first emerge from the cell body and extend along the surface of the sinusoidal capillary, covering it with thin finger-like branches. The perisinusoidal projections are covered with short villi and have characteristic long microshoots that extend even further along the surface of the capillary endothelial tube. Interhepatocellular projections, having overcome the plate of hepatocytes and reaching the adjacent sinusoid, are divided into several perisinusoidal projections. Thus, on average, an Ito cell covers slightly more than two adjacent sinusoids.

When the liver is damaged, Ito cells become activated state. The activated phenotype is characterized by proliferation, chemotaxis, contractility, loss of retinoid stores, and the formation of myofibroblast-like cells. Activated hepatic stellate cells also show increased levels of novel genes such as ICAM-1, chemokines, and cytokines. Activation indicates the onset of the early stage of fibrogenesis and precedes the increased production of ECM proteins. The final stage of liver healing is characterized by increased apoptosis of activated Ito cells, as a result of which their number is sharply reduced.

Gold chloride staining is used to visualize Ito cells under microscopy. It has also been established that a reliable marker for differentiating these cells from other myofibroblasts is their expression of the Reelin protein.

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In 1876, Karl von Kupfer described cells he called "Sternzellen" (stellate cells). When stained with gold oxide, inclusions were visible in the cytoplasm of the cells. Mistakenly considering them to be fragments of red blood cells captured by phagocytosis, Kupfer in 1898 revised his views on the “stellate cell” as a separate type of cell and classified them as phagocytes. However, in subsequent years, descriptions of cells similar to Kupffer's “stellate cells” appeared regularly. They were given various names: interstitial cells, parasinusoid cells, lipocytes, pericytes. The role of these cells remained a mystery for 75 years, until a professor (Toshio Ito) discovered certain cells containing inclusions of fat in the perisinusoidal space of the human liver. Ito called them "shibo-sesshu saibo" - fat-absorbing cells. Realizing that the inclusions were fat produced by cells from glycogen, he changed the name to “shibo-chozo saibo” - fat-storing cells. IN

The main source of endotoxin in the bodyis a gram-negative intestinal flora. Currently, there is no doubt that the liver is the main organ carrying out endotoxin clearance. Endotoxin is taken up primarily by cells kami Kupffer (KK), interacting with the membrane receptor CD 14. Can bind to the receptor itself lipopolysaccharide(LPS), and its complex with lipid A-binding protein com plasma. The interaction of LPS with liver macrophages triggers a cascade of reactions based on the production and release of reduction of cytokines and other biologically active mediators.

There are many publications on the role of macrophgov of the liver (LC) in the uptake and clearance of bacterial LPS, but the interaction of the endothelium with other mesenchymal cells, in particular, with perisinusoidal Ito cells have been practically not studied.

RESEARCH METHODOLOGY

White male rats weighing 200 g were injected intraperitoneally in 1 ml of sterile saline solution highly purified lyophilized LPS E. coli strain 0111 in doses of 0.5,2.5, 10, 25 and 50 mg/kg. At periods of 0.5, 1, 3, 6, 12, 24, 72 hours and 1 week, internal organs were removed under anesthesia and placed in buffered 10% formalin. The material was poured into paraffin blocks. Sections 5 µm thick were stained immunohistochemicalstreptavidin-biotin anti-desmin antibody method, α - smooth- muscle actin (A-GMA) and nuclear antigen well proliferating cells ( PCNA, " Dako"). Desmin was used as a marker perisinusoidalIto cells, A-GMA - as ve marker myofibroblasts, PCNA - proliferating cells. To detect endotoxin in liver cells, purified anti-Re-glycolipidantibodies (Institute of General and Clinical Pathology KDO, Moscow).

RESEARCH RESULTS

At a dosage of 25 mg/kg and higher, fatal shock was observed 6 hours after LPS administration. Acute exposure to LPS on liver tissue caused activation of Ito cells, which was manifested by an increase in their number. Number desmin positive cells increased from 6 hours after LPS injection and reached a maximum ma by 48-72 hours (Fig. 1, a, b).

Rice. 1. Sections of the roof's liver owls, processed LSAB -me- valuableantibodies to des mine(a, b) and α - smooth cervical actin (c), x400 (A, b), x200 (in).

a - before endotoxin administrationon, single desminpositiveIto cells in the periportal zone; b- 72 hoursafter administration of endotoxin on: numerous desminpositive Ito cells; V- 120 hours after administration of en dotoxin: α - smooth muscle active actin is present onlyto smooth muscle cells kah vessels.

In 1 week number desmin positive cells decreased, butwas higher than the control indicators. At In this case, in no case did we observe the appearance A-GMA-positive cells in the sinus give the liver. Internally positive control when stained with antibodies to A-GMA served to identify blood smooth muscle cellsvein vessels of the portal tracts containing A-GMA (Fig. 1, V). Therefore, despite the increase in the number of Ito cells, a one-time exposure to LPS does not lead to transformation ( transdifferentiation) them into myofibroblasts.

Rice. 2. Liver sectionsrats treated LSAB -labeled antibodies to PCNA. a - before the introduction of en dotoxin: singleproliferating genes pathocytes, x200; b - 72 hours after endotoxin administration: numerous proliferating hepatocytes, x400.

Increase in quantity desmin positive cells began within the portal zone. From 6 hours to 24 hours after LPS administration perisinusoidal cells were found only around the portal tracts, i.e. in the 1st zone of ACI noosa. At 48-72 hours, when poppy was observedmaximum quantity desmin positive glue current, they also appeared in other areas of the acinus; nevertheless, most of the Ito cells were still located periportally.

Perhaps this is due to the fact that periportallocated CCs are the first to capture endotoxin coming from the intestine through the portal vein or from the systemic circulation. Ak activated CCs produce a wide spectrum cytokines, which are thought to trigger the activation of Ito cells and transdifferentiation them into myofibroblasts. Obviously, this is why Ito cells located near activated liver macrophages (in the 1st zone of the acinus) are the first to react to the release of cytokines. However, we did not observe them in our study. transdifferentiation V myofibroblasts, and this suggests that cytokines secreted by CC and hepatocytes can serve as a factor supporting the process that has already begun transdifferentiation, but they are probably not able to trigger it with a single exposure of the liver to LPS.

An increase in the proliferative activity of cells was also observed mainly in the 1st zone of the acinus. This probably suggests that all (or almost all) processes aimed at out O- and paracrine regulation of intercellular interactions occur in the periportal zones. An increase in the number of proliferating cells was observed from 24 h after LPS administration; the number of positive cells increased up to 72 hours (maximum proliferative activity, Fig. 2, a, b). Both hepatocytes and sinusoid cells proliferated. However, staining on PCNA does not give the ability to identify the type of proliferation ruminating sinusoid cells. According to the literature, the action of endotoxin leads to increased depending on the amount of CC. They think it's about comes both from the proliferation of liver macrophages and from the migration of monocytes from other organs. Cytokines released by CKs can increase the proliferative capacity of Ito cells. Therefore, it is logical to assume that proliferating cells are represented perisinusoidal Ito cells. The increase in their number that we recorded is apparently necessary to increase the synthesis of growth factors and restore the intercellular matrix under conditions of damage. This may be one of the links in the compensatory-restorative reactions of the liver, since Ito cells are the main source of components of the intercellular matrix, stem cell factor and hepatocyte growth factor, which are involved in repair and differentiation formation of liver epithelial cells. Absent vie transformation of Ito cells into myofibroblasts indicates that one episode of endotoxin aggression is not enough for the development of liver fibrosis.

Thus, the acute effects of endotok syna causes an increase in the number desmin positive Ito cells, which is an indirect sign of liver damage. Quantity perisinusoidal cells increases, apparently as a result of their proliferation. A single episode of endotoxin aggression causes reverse my activation perisinusoidal Ito cells and does not lead to them transdifferentiation into myofibroblasts. In this regard, it can be assumed that in the mechanisms of activation and transdifferentiation Ito cells involve not only endotoxin and cytokines, but also some other factors of intercellular interactions.

LITERATURE

1. Mayansky D.N., Wisse E., Decker K. // New frontiers hepatology. Novosibirsk, 1992.

2. Salakhov I.M., Ipatov A.I., Konev Yu.V., Yakovlev M.Yu. // We will make progress, biol. 1998. T. 118, Issue. 1. pp. 33-49.

3. Yakovlev M.Yu. // Kazan . m units magazine 1988. No. 5. P. 353-358.

4. Freudenberg N., Piotraschke J., Galanos C. et al. // Virchows Arch. [B]. 1992. Vol. 61.P. 343-349.

5. Gressner A. M. // Hepatogastronterology. 1996. Vol. 43. P. 92-103.

6. Schmidt C, Bladt F., Goedecke S. et al. // Nature. 1995. Vol. 373, N 6516. P. 699-702.

7. Wisse E., Braet F., Luo D. et al. // Toxicol. Pathol. 1996. Vol. 24, N 1. P. 100-111.

In this case, these cells respond by multiplying to the influence of cytokines, growth factors and chemokines (pro-inflammatory cytokines) produced by the damaged liver. Chronic activation of stellate cells in response to oxidative stress caused by HBV and HCV virus replication may contribute to fibrogenesis and increased proliferation of hepatocytes chronically infected with HBV and HCV.

Thus, stellate cells take part in the regulation of growth, differentiation and turnover of hepatocytes, which, together with the activation of MAP kinases, can lead to the development of liver cancer [Block, 2003].

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Studying the influence of liver Ito cells on stem cells

Intercellular communication might be realized by paracrine secretion and direct cell-to-cell contacts. It is known that hepatic perisinusoidal cells (HPC) establish regional stem cells niche and determine their differentiation. At the same time, HPC remains poorly characterized on molecular and cellular level.

Shafigullina A.K., Trondin A.A., Shaikhutdinova A.R., Kaligin M.S., Gazizov I.M., Rizvanov A.A., Gumerova A.A., Kiyasov A.P.

State Educational Institution of Higher Professional Education "Kazan State Medical University of the Federal Agency for Health and Social Development"

Experimental assessment of osteoinductivity of recombinant bone morphogenetic protein

Cellular technologies in the treatment of degenerative diseases of bones and joints

Ito cage

calm And activated. Activated Ito cells

calm state

perisinusoidal(subendothelial) and interhepatocellular. The first leave the cell body and extend along the surface of the sinusoidal capillary, covering it with thin finger-like branches. The perisinusoidal projections are covered with short villi and have characteristic long microshoots that extend even further along the surface of the capillary endothelial tube. Interhepatocellular projections, having overcome the plate of hepatocytes and reaching the adjacent sinusoid, are divided into several perisinusoidal projections. Thus, on average, an Ito cell covers slightly more than two adjacent sinusoids.

activated state

Liver cells

The human liver is made up of cells, like any organic tissue. Nature has designed it in such a way that this organ performs the most important functions: it cleanses the body, produces bile, accumulates and deposits glycogen, synthesizes plasma proteins, manages metabolic processes, and participates in normalizing the amount of cholesterol and other components necessary for the functioning of the body.

To fulfill their purpose, liver cells must be healthy, have a stable structure, and each person must protect them from destruction.

About the structure and types of liver lobules

The cellular composition of the organ is characterized by diversity. Liver cells form lobules, and segments are made up of lobules. The structure of the organ is such that hepatocytes (the main liver cells) are located around the central vein, branch from it, connect with each other, forming sinusoids, that is, gaps filled with blood. Blood moves through them as if through capillaries. The liver is supplied with blood from the portal vein and artery located in the organ. The liver lobules produce bile and discharge it into the flow channels.

Other types of liver cells and their purpose

Endothelial - cells lining the sinusoids and containing fenestrae. The latter are intended to form a stepped barrier between the sinusoid and the Disse space.
The space of Disse itself is filled with stellate cells; they ensure the outflow of tissue fluid into the lymph vessels of the portal zones.
Kupffer cells are associated with the endothelium, they are attached to it, their function is to protect the liver when a generalized infection enters the body, or during injury.
Pit cells are killers of hepatocytes affected by the virus; in addition, they have cytotoxicity to tumor cells.

The human liver consists of 60% hepatocytes and 40% other types of cellular compounds. Hepatocytes have a polyhedron shape; there are at least 250 billion of them. The normal functioning of hepatocytes is determined by the spectrum of components that are secreted by the sinusoidal cells that fill the sinusoidal compartment. That is, the Kupffer listed above, stellate and pit cells (intrahepatic lymphocytes).

The endothelial is a filter between the blood in the sinusoidal space and the plasma in the Disse space. This biological filter sorts out large compounds that are excessively rich in retinol and cholesterol and does not allow them to pass through, which is beneficial for the body. In addition, their function is to protect the liver (namely hepatocytes) from mechanical damage by blood cells.

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The process of interaction of organ elements

There is an interaction between all particles of the organ, which has a rather complex scheme. A healthy liver is characterized by the stability of cellular connections; in pathological processes, the extracellular matrix can be traced under a microscope.

Organ tissue undergoes changes under the influence of toxins, for example, alcohol, viral agents. They are as follows:

deposition in the organ of products formed due to metabolic disorders;
cell degeneration;
hepatocyte necrosis;
fibrosis of liver tissue;
inflammatory process of the liver;
cholestasis.

About the treatment of organ pathology

It is useful for each patient to know what the changes that the organ undergoes mean. Not all of them are catastrophic. For example, dystrophy can be mild or severe. Both of these processes are reversible. Currently, there are drugs that restore cells and entire segments of the liver.

Cholestasis can be cured even with folk remedies - decoctions and infusions. They help normalize the synthesis of bilirubin and eliminate disturbances in the outflow of bile into the duodenum.

For cirrhosis in the initial stage, treatment begins with a diet, then hepatoprotector therapy is prescribed. The most effective way to treat cirrhosis and fibrosis is stem cells, which are injected into the umbilical vein or intravenously; they restore hepatocytes damaged by various agents.

The main causes of liver cell death are alcohol abuse and drug exposure, including drugs and medications. Any toxin that enters the body is a liver destroyer. Therefore, you should give up bad habits so that you have a healthy liver.

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Education: Rostov State Medical University (RostSMU), Department of Gastroenterology and Endoscopy.

ENDOTHELIAL CELLS, KUPFER CELLS AND ITO

We will look at the structure of endothelial cells, Kupffer and Ito cells, using the example of two drawings.

The figure to the right of the text shows the sinusoidal capillaries (SC) of the liver - intralobular capillaries of the sinusoidal type, increasing from the entrance venules to the central vein. Hepatic sinusoidal capillaries form an anastomotic network between the hepatic plates. The lining of sinusoidal capillaries is formed by endothelial cells and Kupffer cells.

In the figure to the left of the text, the hepatic plate (LP) and the two sinusoidal capillaries (SCs) of the liver are cut vertically and horizontally to show the perisinusoidal Ito cells (Ito cells). The cut bile canaliculi (BC) are also marked in the figure.

ENDOTHELIAL CELLS

Endothelial cells (EC) are highly flattened squamous cells with an elongated small nucleus, poorly developed organelles and a large number of micropinocytotic vesicles. The cytomembrane is dotted with irregular openings (O) and fenestrae, often grouped into cribriform plates (RP). These holes allow blood plasma to pass through, but not blood cells, allowing it access to hepatocytes (D). Endothelial cells do not have a basement membrane and do not exhibit phagocytosis. They are connected to each other using small connecting complexes (not shown). Together with Kupffer cells, endothelial cells form the internal border of the space of Disse (PD); its outer border is formed by hepatocytes.

KUPFER CELLS

Kupffer cells (KCs) are large, non-persistent stellate cells within the hepatic sinusoidal capillaries, partly at their bifurcations.

Kupffer cell processes pass without any connecting devices between endothelial cells and often cross the lumen of the sinusoids. Kupffer cells contain an oval nucleus, many mitochondria, a well-developed Golgi complex, short cisterns of granular endoplasmic reticulum, many lysosomes (L), residual bodies and rare annular plates. Kupffer cells also include large phagolysosomes (PLs), which often contain obsolete red blood cells and foreign substances. Inclusions of hemosiderin or iron can also be detected, especially with supravital staining.

The surface of Kupffer cells displays variable, flattened cytoplasmic folds called lamellipodia (LP) - lamellar stalks - as well as processes called filopodia (F) and microvilli (MV) covered with glycocalyx. The plasmalemma forms vermiform bodies (VB) with a centrally located dense line. These structures may represent a condensed glycocalyx.

Kupffer cells are macrophages, very likely forming an independent genus of cells. They usually originate from other Kupffer cells due to mitotic division of the latter, but can also originate from the bone marrow. Some authors believe that they are activated endothelial cells.

Occasionally, an occasional autonomic nerve fiber (ANF) passes through the space of Disse. In some cases, the fibers have contact with hepatocytes. The edges of hepatocytes are delimited by interhepatocyte recesses (MU) dotted with microvilli.

ITO CELLS

These are stellate cells localized within the spaces of Disse (SD). Their nuclei are rich in condensed chromatin and are usually deformed by large lipid droplets (LDs). The latter are present not only in the perikaryon, but also in the processes of the cell and are visible from the outside as spherical protrusions. Organelles are poorly developed. Perisinusoidal cells show weak endocytotic activity but do not possess phagosomes. The cells have several long processes (O) that contact neighboring hepatocytes, but do not form connecting complexes.

The processes envelop the sinusoidal capillaries of the liver and in some cases pass through the hepatic plates, coming into contact with adjacent hepatic sinusoids. The processes are not constant, branched and thin; they can also be flattened. By accumulating groups of lipid droplets, they lengthen and take on the appearance of a bunch of grapes.

It is believed that perisinusoidal Ito cells are poorly differentiated mesenchymal cells that can be considered hematopoietic stem cells, since they can transform into fat cells, active blood stem cells or fibroblasts under pathological conditions.

Under normal conditions, Ito cells are involved in the accumulation of fat and vitamin A as well as in the production of intralobular reticular and collagen fibers (KB).

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Ito liver cells

Universal popular science online encyclopedia

LIVER

LIVER, the largest gland in the body of vertebrates. In humans, it makes up about 2.5% of body weight, on average 1.5 kg in adult men and 1.2 kg in women. The liver is located in the upper right part of the abdominal cavity; it is attached by ligaments to the diaphragm, abdominal wall, stomach and intestines and is covered with a thin fibrous membrane - Glisson's capsule. The liver is a soft but dense organ of a red-brown color and usually consists of four lobes: a large right lobe, a smaller left lobe and much smaller caudate and quadrate lobes that form the posterior lower surface of the liver.

Functions.

The liver is an essential organ for life with many different functions. One of the main ones is the formation and secretion of bile, a transparent liquid of orange or yellow color. Bile contains acids, salts, phospholipids (fats containing a phosphate group), cholesterol and pigments. Bile salts and free bile acids emulsify fats (i.e. break them into small droplets), making them easier to digest; convert fatty acids into water-soluble forms (which is necessary for the absorption of both the fatty acids themselves and fat-soluble vitamins A, D, E and K); have an antibacterial effect.

All nutrients absorbed into the blood from the digestive tract - products of the digestion of carbohydrates, proteins and fats, minerals and vitamins - pass through the liver and are processed there. At the same time, some amino acids (protein fragments) and some fats are converted into carbohydrates, so the liver is the largest “depot” of glycogen in the body. It synthesizes blood plasma proteins - globulins and albumin, and also undergoes amino acid conversion reactions (deamination and transamination). Deamination - the removal of nitrogen-containing amino groups from amino acids - allows the latter to be used, for example, for the synthesis of carbohydrates and fats. Transamination is the transfer of an amino group from an amino acid to a keto acid to form another amino acid ( cm. METABOLISM). The liver also synthesizes ketone bodies (products of fatty acid metabolism) and cholesterol.

The liver is involved in regulating glucose (sugar) levels in the blood. If this level increases, liver cells convert glucose into glycogen (a substance similar to starch) and store it. If the blood glucose level drops below normal, glycogen is broken down and glucose enters the bloodstream. In addition, the liver is capable of synthesizing glucose from other substances, such as amino acids; this process is called gluconeogenesis.

Another function of the liver is detoxification. Medicines and other potentially toxic compounds can be converted into a water-soluble form in liver cells, which allows them to be excreted in bile; they can also be destroyed or conjugate (combine) with other substances to form harmless products that are easily excreted from the body. Some substances are temporarily deposited in Kupffer cells (special cells that absorb foreign particles) or in other liver cells. Kupffer cells are particularly effective at removing and destroying bacteria and other foreign particles. Thanks to them, the liver plays an important role in the body's immune defense. Possessing a dense network of blood vessels, the liver also serves as a blood reservoir (it constantly contains about 0.5 liters of blood) and is involved in the regulation of blood volume and blood flow in the body.

In general, the liver performs more than 500 different functions, and its activity cannot yet be reproduced artificially. Removal of this organ inevitably leads to death within 1–5 days. However, the liver has a huge internal reserve, it has an amazing ability to recover from damage, so humans and other mammals can survive even after 70% of the liver tissue is removed.

Structure.

The complex structure of the liver is perfectly adapted to perform its unique functions. The lobes consist of small structural units - lobules. In the human liver there are about one hundred thousand of them, each 1.5–2 mm long and 1–1.2 mm wide. The lobule consists of liver cells - hepatocytes, located around the central vein. Hepatocytes are united into layers one cell thick - the so-called. liver plates. They diverge radially from the central vein, branch and connect with each other, forming a complex system of walls; the narrow gaps between them, filled with blood, are known as sinusoids. Sinusoids are equivalent to capillaries; passing one into another, they form a continuous labyrinth. The hepatic lobules are supplied with blood from the branches of the portal vein and hepatic artery, and the bile formed in the lobules enters the tubular system, from them into the bile ducts and is excreted from the liver.

The hepatic portal vein and hepatic artery provide the liver with an unusual, dual blood supply. Nutrient-rich blood from the capillaries of the stomach, intestines and several other organs is collected in the portal vein, which, instead of carrying blood to the heart like most other veins, carries it to the liver. In the liver lobules, the portal vein breaks up into a network of capillaries (sinusoids). The term “portal vein” indicates an unusual direction of blood transport from the capillaries of one organ to the capillaries of another (the kidneys and pituitary gland have a similar circulatory system).

The second source of blood supply to the liver, the hepatic artery, carries oxygenated blood from the heart to the outer surfaces of the lobules. The portal vein provides 75–80%, and the hepatic artery 20–25% of the total blood supply to the liver. In general, about 1500 ml of blood passes through the liver per minute, i.e. a quarter of cardiac output. Blood from both sources ultimately enters the sinusoids, where it mixes and flows to the central vein. From the central vein, the outflow of blood to the heart begins through the lobar veins into the hepatic vein (not to be confused with the portal vein of the liver).

Bile is secreted by liver cells into the smallest tubules between the cells - bile capillaries. It is collected through the internal system of tubules and ducts into the bile duct. Some bile goes directly into the common bile duct and is released into the small intestine, but most of it travels through the cystic duct back for storage in the gallbladder, a small, muscular-walled sac attached to the liver. When food enters the intestines, the gallbladder contracts and releases the contents into the common bile duct, which opens into the duodenum. The human liver produces about 600 ml of bile per day.

Portal triad and acini.

The branches of the portal vein, hepatic artery and bile duct are located nearby, at the outer border of the lobule and form the portal triad. At the periphery of each lobule there are several such portal triads.

The functional unit of the liver is the acinus. This is the part of tissue that surrounds the portal triad and includes lymphatic vessels, nerve fibers and adjacent sectors of two or more lobules. One acini contains about 20 liver cells located between the portal triad and the central vein of each lobule. In a two-dimensional image, a simple acinus looks like a group of vessels surrounded by adjacent sections of lobules, and in a three-dimensional image it looks like a berry (acinus - lat. berry) hanging on a stalk of blood and bile vessels. The acini, the microvascular framework of which consists of the above-mentioned blood and lymphatic vessels, sinusoids and nerves, is the microcirculatory unit of the liver.

Liver cells

(hepatocytes) have the shape of polyhedra, but they have three main functional surfaces: sinusoidal, facing the sinusoidal channel; tubular - involved in the formation of the wall of the bile capillary (it does not have its own wall); and intercellular - directly adjacent to neighboring liver cells.

Ito cage

Ito cells (synonyms: hepatic stellate cell, fat-storing cell, lipocyte, English. Hepatic Stellate Cell, HSC, Cell of Ito, Ito cell) - pericytes contained in the perisinusoidal space of the hepatic lobule, capable of functioning in two different states - calm And activated. Activated Ito cells play a major role in fibrogenesis - the formation of scar tissue in liver damage.

In an intact liver, stellate cells are found in calm state. In this state, the cells have several projections covering the sinusoidal capillary. Another distinctive feature of cells is the presence of vitamin A (retinoid) reserves in their cytoplasm in the form of fat droplets. Quiet Ito cells make up 5-8% of all liver cells.

Ito cell outgrowths are divided into two types: perisinusoidal(subendothelial) and interhepatocellular. The first leave the cell body and extend along the surface of the sinusoidal capillary, covering it with thin finger-like branches. The perisinusoidal projections are covered with short villi and have characteristic long microshoots that extend even further along the surface of the capillary endothelial tube. Interhepatocellular projections, having overcome the plate of hepatocytes and reaching the adjacent sinusoid, are divided into several perisinusoidal projections. Thus, on average, an Ito cell covers slightly more than two adjacent sinusoids.

When the liver is damaged, Ito cells become activated state. The activated phenotype is characterized by proliferation, chemotaxis, contractility, loss of retinoid stores, and the formation of myofibroblast-like cells. Activated hepatic stellate cells also show increased levels of novel genes such as α-SMA, ICAM-1, chemokines, and cytokines. Activation indicates the onset of the early stage of fibrogenesis and precedes the increased production of ECM proteins. The final stage of liver healing is characterized by increased apoptosis of activated Ito cells, as a result of which their number is sharply reduced.

Story

In 1876, Karl von Kupfer described cells he called "Sternzellen" (stellate cells). When stained with gold oxide, inclusions were visible in the cytoplasm of the cells. Mistakenly considering them to be fragments of red blood cells captured by phagocytosis, Kupfer in 1898 revised his views on the “stellate cell” as a separate type of cell and classified them as phagocytes. However, in subsequent years, descriptions of cells similar to Kupffer's “stellate cells” appeared regularly. They were given various names: interstitial cells, parasinusoid cells, lipocytes, pericytes. The role of these cells remained a mystery for 75 years, until Professor Toshio Ito discovered certain cells containing fat inclusions in the perisinusoidal space of the human liver. Ito called them "shibo-sesshu saibo" - fat-absorbing cells. Realizing that the inclusions were fat produced by cells from glycogen, he changed the name to “shibo-chozo saibo” - fat-storing cells. In 1971, Kenjiro Wake proved the identity of Kupffer's Sternzellen and Ito's fat-storing cells. Vake also found that these cells play an important role in storing vitamin A (prior to this it was believed that vitamin A was stored in Kupffer cells). Shortly thereafter, Kent and Popper demonstrated the close association of Ito cells with liver fibrosis. These discoveries began the process of studying Ito cells in detail.

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Links

Young-O Queon, Zachary D. Goodman, Jules L. Dienstag, Eugene R. Schiff, Nathaniel A. Brown, Elmar Burkhardt, Robert Schoonhoven, David A. Brenner, Michael W. Fried (2001). Journal of Haepothology 35; 749-755. - translation of an article in the journal “Infections and Antimicrobial Therapy”, Volume 04/N 3/2002, on the Consilium-Medicum website.
Popper H: Distribution of vitamin A in tissue as revealed by fluorescence microscopy. Physiol Rev 1944, 24:.

Notes

Geerts A. (2001) History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis. 21(3):311-35. PMID
Wake, K. (1988) Liver perivascular cells revealed by gold- and silver-impregnation method and electron microscopy. In “Biopathology of the Liver. An Ultrastructural Approach" (Motta, P. M., ed) pp. 23-36, Kluwer Academic Publishers, Dordrecht, Netherlands
Stanciu A, Cotutiu C, Amalinei C. (2002) New data about ITO cells. Rev Med Chir Soc Med Nat Iasi. 107(2):235-9. PMID
John P. Iredale (2001) Hepatic Stellate Cell Behavior During Resolution of Liver Injury. Seminars in Liver Disease, 21(3):PMID- (English) on Medscape.
Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, Steffgen J, Ramadori G, Knittel T. (2002) Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J Hepatol. 36(5):607-13. PMID
Adrian Reuben (2002) Hepatology. Volume 35, Issue 2, Pages 503-504 (English)
Suematsu M, Aiso S. (2001) Professor Toshio Ito: a clairvoyant in pericyte biology. Keio J Med. 50(2):66-71. PMID (English)
Querner F: Der mikroskopische Nachweis von Vitamin A im animalen Gewebe. Zur Kenntnis der paraplasmatischen Leberzellen-einschlüsse. Dritte Mitteilung. Klin Wschr 1935, 14:.

Excerpt characterizing Ito's Cell

Half an hour later, Kutuzov left for Tatarinova, and Bennigsen and his retinue, including Pierre, went along the line.

Bennigsen from Gorki descended along the high road to the bridge, which the officer from the mound pointed out to Pierre as the center of the position and on the bank of which lay rows of mown grass that smelled of hay. They drove across the bridge to the village of Borodino, from there they turned left and past a huge number of troops and cannons they drove out to a high mound on which the militia was digging. It was a redoubt that did not yet have a name, but later received the name Raevsky redoubt, or barrow battery.

Pierre did not pay much attention to this redoubt. He did not know that this place would be more memorable for him than all the places in the Borodino field. Then they drove through the ravine to Semenovsky, in which the soldiers were taking away the last logs of the huts and barns. Then, downhill and uphill, they drove forward through broken rye, knocked out like hail, along a road newly laid by artillery along the ridges of arable land to the flushes [a type of fortification. (Note by L.N. Tolstoy.) ], also still being dug at that time.

Bennigsen stopped at the flushes and began to look ahead at the Shevardinsky redoubt (which was ours only yesterday), on which several horsemen could be seen. The officers said that Napoleon or Murat was there. And everyone looked greedily at this bunch of horsemen. Pierre also looked there, trying to guess which of these barely visible people was Napoleon. Finally, the riders rode off the mound and disappeared.

Bennigsen turned to the general who approached him and began to explain the entire position of our troops. Pierre listened to Bennigsen's words, straining all his mental strength to understand the essence of the upcoming battle, but he felt with disappointment that his mental abilities were insufficient for this. He didn't understand anything. Bennigsen stopped talking, and noticing the figure of Pierre, who was listening, he suddenly said, turning to him:

– I think you’re not interested?

“Oh, on the contrary, it’s very interesting,” Pierre repeated, not entirely truthfully.

From the flush they drove even further to the left along a road winding through a dense, low birch forest. In the middle of it

forest, a brown hare with white legs jumped out onto the road in front of them and, frightened by the clatter of a large number of horses, he was so confused that he jumped along the road in front of them for a long time, arousing everyone’s attention and laughter, and only when several voices shouted at him, he rushed to the side and disappeared into the thicket. After driving about two miles through the forest, they came to a clearing where the troops of Tuchkov’s corps, which was supposed to protect the left flank, were stationed.

Here, on the extreme left flank, Bennigsen spoke a lot and passionately and made, as it seemed to Pierre, an important military order. There was a hill in front of Tuchkov’s troops. This hill was not occupied by troops. Bennigsen loudly criticized this mistake, saying that it was crazy to leave the height commanding the area unoccupied and place troops under it. Some generals expressed the same opinion. One in particular spoke with military fervor about the fact that they were put here for slaughter. Bennigsen ordered in his name to move the troops to the heights.

This order on the left flank made Pierre even more doubtful of his ability to understand military affairs. Listening to Bennigsen and the generals condemning the position of the troops under the mountain, Pierre fully understood them and shared their opinion; but precisely because of this, he could not understand how the one who placed them here under the mountain could make such an obvious and gross mistake.

Pierre did not know that these troops were not placed to defend the position, as Bennigsen thought, but were placed in a hidden place for an ambush, that is, in order to be unnoticed and suddenly attack the advancing enemy. Bennigsen did not know this and moved the troops forward for special reasons without telling the commander-in-chief about it.

On this clear August evening on the 25th, Prince Andrei lay leaning on his arm in a broken barn in the village of Knyazkova, on the edge of his regiment’s location. Through the hole in the broken wall, he looked at a strip of thirty-year-old birch trees with their lower branches cut off running along the fence, at an arable land with stacks of oats broken on it, and at bushes through which the smoke of fires—soldiers’ kitchens—could be seen.

No matter how cramped and no one needed and no matter how difficult his life now seemed to Prince Andrei, he, just like seven years ago at Austerlitz on the eve of the battle, felt agitated and irritated.

Orders for tomorrow's battle were given and received by him. There was nothing else he could do. But the simplest, clearest thoughts and therefore terrible thoughts did not leave him alone. He knew that tomorrow's battle was going to be the most terrible of all those in which he participated, and the possibility of death for the first time in his life, without any regard to everyday life, without consideration of how it would affect others, but only according to in relation to himself, to his soul, with vividness, almost with certainty, simply and horribly, it presented itself to him. And from the height of this idea, everything that had previously tormented and occupied him was suddenly illuminated by a cold white light, without shadows, without perspective, without distinction of outlines. His whole life seemed to him like a magic lantern, into which he looked for a long time through glass and under artificial lighting. Now he suddenly saw, without glass, in bright daylight, these poorly painted pictures. “Yes, yes, these are the false images that worried and delighted and tormented me,” he said to himself, turning over in his imagination the main pictures of his magic lantern of life, now looking at them in this cold white light of day - a clear thought of death. “Here they are, these crudely painted figures that seemed to be something beautiful and mysterious. Glory, public good, love for a woman, the fatherland itself - how great these pictures seemed to me, what deep meaning they seemed filled with! And all this is so simple, pale and rough in the cold white light of that morning, which I feel is rising for me. Three major sorrows of his life in particular occupied his attention. His love for a woman, the death of his father and the French invasion that captured half of Russia. "Love. This girl seemed to me full of mysterious powers. How I loved her! I made poetic plans about love, about happiness with it. Oh dear boy! – he said out loud angrily. - Of course! I believed in some kind of ideal love, which was supposed to remain faithful to me during the whole year of my absence! Like the tender dove of a fable, she was to wither away in separation from me. And all this is much simpler... All this is terribly simple, disgusting!

Keywords

LIVER / STELLATE CELLS ITO/ MORPHOLOGY / CHARACTERISTIC / VITAMIN A / FIBROSIS / LIVER / HEPATIC STELLATE CELLS / MORPHOLOGY / CHARACTERISTIC / VITAMIN A / FIBROSIS

annotation scientific article on fundamental medicine, author of the scientific work - Tsyrkunov V.M., Andreev V.P., Kravchuk R.I., Kondratovich I.A.

Introduction. The role of Ito stellate cells (ISC) has been identified as one of the leading ones in the development of fibrosis in the liver, however, intravital visualization of the ISC structure is minimally used in clinical practice. Purpose of the work: to present the structural and functional characteristics of PCI based on the results of cytological identification of intravital liver biopsies. Materials and methods. Classical methods of light and electron microscopy of biopsy specimens and original techniques using ultrathin sections, fixation and staining were used. Results. Photo illustrations of light and electron microscopy of liver biopsies from patients with chronic hepatitis C show the structural characteristics of PCIs at different stages (rest, activation) and in the process of transformation into myofibroblasts. Conclusions. The use of original methods for clinical morphological identification and assessment of the functional state of the liver will improve the quality of diagnosis and prognosis of liver fibrosis.

Text of scientific work on the topic “Clinical Liver Cytology: Ito stellate cells”

UDC 616.36-076.5

CLINICAL CYTOLOGY OF THE LIVER: ITO STELLATE CELLS

Tsyrkunov V. M. ( [email protected]), Andreev V. P. ( [email protected]), Kravchuk R. I. ( [email protected]), Kondratovich I. A. ( [email protected]) EE "Grodno State Medical University", Grodno, Belarus

Purpose of the work: to present the structural and functional characteristics of PCI based on the results of cytological identification of intravital liver biopsies.

Materials and methods. Classical methods of light and electron microscopy of biopsy specimens and original techniques using ultrathin sections, fixation and staining were used.

Results. Photo illustrations of light and electron microscopy of liver biopsies from patients with chronic hepatitis C show the structural characteristics of PCIs at different stages (rest, activation) and in the process of transformation into myofibroblasts.

Conclusions. The use of original methods for clinical morphological identification and assessment of the functional state of the liver will improve the quality of diagnosis and prognosis of liver fibrosis.

Key words: liver, Ito stellate cells, morphology, characteristics, vitamin A, fibrosis.

Introduction

An unfavorable outcome of most chronic diffuse liver lesions of various etiologies, including chronic hepatitis C (CHC), is liver fibrosis, in the development of which the main participants are activated fibroblasts, the main source of which are activated Ito stellate cells (Ito stellate cells).

Hepatic Stellate Cell, HSC, Cell of Ito, Ito cell. ZCIs were first described in 1876 by K. Kupffer and named by him stellate cells (“Stemzellen”). T. Ito, having discovered drops of fat in them, first designated them fat-absorbing (“shibo-sesshusaibo”), and then, having established that fat was produced by the cells themselves from glycogen, fat-storing cells (“shibo-chozosaibo”) . In 1971, K. Wake proved the identity of Kupfffer stellate cells and Ito fat-storing cells and that these cells “store” vitamin A.

About 80% of vitamin A in the body accumulates in the liver, and up to 80% of all liver retinoids are deposited in fat droplets of the liver. Retinol esters in the composition of chylomicrons enter hepatocytes, where they are converted into retinol, forming a complex of vitamin A with retinol binding protein (RBP), which is secreted into the perisinusoidal space, from where it is deposited by the cells.

The close connection between PCI and liver fibrosis established by K. Popper demonstrated their not static, but dynamic function - the ability to directly participate in the remodeling of the intralobular perihepatocellular matrix.

The main method of morphological examination of the liver, carried out to assess changes in intravital biopsies, is light microscopy, which in clinical practice makes it possible to determine the activity of the liver.

burning and the stage of chronicity. The disadvantage of the method is its low resolution, which does not allow one to evaluate the structural features of cells, intracellular organelles, inclusions, and functional characteristics. Intravital electron microscopic examination of ultrastructural changes in the liver makes it possible to supplement light microscopy data and increase their diagnostic value.

In this regard, the identification of liver HCIs, the study of their phenotype in the process of transdifferentiation, and the determination of the intensity of their proliferation are the most important contribution to predicting the outcomes of liver diseases, as well as to the pathomorphology and pathophysiology of fibrogenesis.

The goal is to present the structural and functional characteristics of PCI based on the results of cytological identification of intravital liver biopsies.

Materials and methods

Intravital liver biopsy was obtained by performing liver aspiration biopsy in patients with CHC (HCV RNA+), from whom written informed consent was obtained.

For light microscopy of semi-thin sections, liver biopsy samples of patients measuring 0.5-2 mm were fixed using a double fixation method: first - according to the Sato Taizan method, then tissue samples were additionally fixed for 1 hour in 1% osmium fixative prepared in 0.1 M phosphate Sorensen buffer, pH 7.4. To better identify intracellular structures and interstitial substances on semi-thin sections, potassium dichromate (K2Cr2O7) or chromic anhydride crystals (1 mg/ml) were added to 1% osmium tetroxide. After dehydration of the samples in a series of alcohol solutions of increasing concentrations and acetone, they were placed in a prepolymerized mixture of butyl methacrylate and styrene and polymerized at 550C. Semi-thin sections (1 µm thick) were sequentially stained

azure II-basic fuchsin. Microphotographs were taken using a digital video camera (Leica FC 320, Germany).

Electron microscopic examination was carried out in liver biopsy samples measuring 0.5x1.0 mm, fixed with a 1% solution of osmium tetroxide in 0.1 M Milloniga buffer, pH 7.4, at +40C for 2 hours. After dehydration in ascending alcohols and acetone, the samples were embedded in Araldite. Semi-thin sections (400 nm) were prepared from the resulting blocks using a Leica EM VC7 ultramicrotome (Germany) and stained with methylene blue. The preparations were examined under a light microscope and a similar area was selected for further study of ultrastructural changes. Ultrathin sections (35 nm) were counterstained with 2% uranyl acetate in 50% methanol and lead citrate according to E. S. Reynolds. Electron microscopic preparations were studied in a JEM-1011 electron microscope (JEOL, Japan) at magnifications of 10,000-60,000 and an accelerating voltage of 80 kW. To obtain images, a complex consisting of an Olympus MegaViewIII digital camera (Germany) and iTEM image processing software (Olympus, Germany) was used.

Results and discussion

PCIs are located in the perisinusoidal space (Disse) in pockets between hepatocytes and endothelial cells, and have long processes that penetrate deeply between hepatocytes. Most publications devoted to this population of CCIs provide their schematic representation, which only allows one to indicate the “territorial” affiliation of CCIs in the liver and in relation to the surrounding “neighbors” (Figure 1).

PCIs have close contact with endothelial cells through components of the incomplete basement membrane and interstitial collagen fibers. Nerve endings penetrate between the PCI and parenchymal cells, which is why the space of Disse is defined as the space between the plates of parenchymal cells and

complex of HCI and endothelial cells.

It is believed that PCIs originate from poorly differentiated mesenchymal cells of the transverse septum of the developing liver. The experiment established that hematopoietic stem cells participate in the formation of HCI and that this process is not caused by cell fusion.

Sinusoidal cells (SCs), primarily HSCs, play a leading role in all types of liver regeneration. Fibrosing liver regeneration occurs as a result of inhibition of the stem functions of the liver and bone marrow stem cells. In the human liver, HSCs account for 5-15%, being one of 4 types of SCs that are of mesenchymal origin: Kupffer cells, endothelial cells, Pd cells. The SC pool also contains 20-25% leukocytes.

The cytoplasm of the HCI contains fatty inclusions with retinol, triglycerides, phospholipids, cholesterol, free fatty acids, α-actin and desmin. Gold chloride staining is used to visualize PCI. The experiment established that a marker of differentiation of HCI from other myofibroblasts is their expression of the Reelin protein.

HSCs exist in a quiet (“inactive HSC”), transient, and long-term activated states, each of which is characterized by gene expression and phenotype (α-MA, ICAM-1, chemokines and cytokines).

In an inactive state, HCIs have a round, slightly elongated or irregular shape, a large core and a clear visual feature - lipid inclusions (droplets) containing retinol (Figure 2).

The number of lipid droplets in the inactive HCI reaches 30 or more; they are close in size, adjacent to each other, pressing into the core and pushing it to the periphery (Figure 2). Small inclusions may be located between large drops. The color of the drops depends on the fixative and the color of the material. In one case they are light (Figure 2a), in the other they are dark green (Figure 2b).

Figure 1. - Scheme of the location of the PCI (stellatecell, perisinusoidal lipocyte) in the perisinusoidal space of Disse (space of Disse), Internet resource

Figure 2. - ZKI in an inactive state

a - round-shaped HCI with a high content of lipid droplets with a light color (white arrows), hepatocytes (Hz) with devastated cytoplasm (black arrow); b - HCI with dark-colored lipid droplets, in close contact with the macrophage (Mph); a-b - semi-thin sections. The color of azure II is basic magenta. Microphotographs. Increased 1000; c - ZCI with an abundance of lipid droplets (more than 30), having an irregular shape (magnitude 6,000); d-ultrastructural components of the ICI: l-lipid droplets, mitochondria (orange arrows), GRES (green arrows), Golgi complex (red arrow), uv. 15,000; v-d - electron diffraction patterns

With electron microscopy, a more osmiophilic marginal rim is formed against the background of a light lipid substrate (Figure 5a). In most “resting” HCIs, along with large lipid inclusions, there is a noticeably small amount of cytoplasmic matrix, poor in mitochondria (Mx) and granular endoplasmic reticulum (GRE). In this case, the compartments of a moderately developed Golgi complex are clearly visible in the form of a stack of 3-4 flattened cisterns with slightly widened ends (Figure 2d).

Under certain conditions, activated HSCs acquire a mixed or transitional phenotype, combining the morphological characteristics of both lipid-containing and fibroblast-like cells (Figure 3).

The transitional phenotype of PCI also has its own morphological characteristics. The cell acquires an elongated shape, the number of lipid inclusions decreases, and the number of invaginations of the nucleolemma decreases. The volume of the cytoplasm increases, containing numerous cisterns of the GES with bound ribosomes and free ribosomes, Mx. Hyperplasia of the components of the lamellar Golgi complex, represented by several stacks of 3-8 flattened cisterns, is observed; the number of lysosomes involved in the degradation increases.

Figure 3. - ZKIs in a transition state

a - ZKI (white arrows). Semi-thin slice. The color of azure II is basic magenta. Microphotography. Increased 1000; b - ZCI of an elongated shape and with a small number of lipid droplets; uv. 8,000; c - ZCI in contact with Kupffer cells (KC) and lymphocyte (Lc), uv. 6,000. (Hz - hepatocyte, l - lipid drops, E - erythrocyte); d - mitochondria (orange arrows), GRES (green arrows), Golgi cell (red arrow), lysosomes (blue arrows), level 20,000; b, c, d - electron diffraction patterns

tion of lipid droplets (Figure 3d). Hyperplasia of the components of the GRES and the Golgi complex is associated with the ability of fibroblasts to synthesize collagen molecules, as well as to model them through post-translational hydroxylation and glycosylation in the endoplasmic reticulum and elements of the Golgi complex.

In an undamaged liver, the PCI, being in a calm state, covers the sinusoidal capillary with its processes. The processes of the PCI are divided into 2 types: perisinusoidal (subendothelial) and interhepatocellular (Figure 4).

The first leave the cell body and extend along the surface of the sinusoidal capillary, covering it with thin finger-like branches. They are covered with short villi and have characteristic long micro-ejections that extend even further along the surface of the endothelial tube of the capillary. Interhepatocellular projections, having overcome the plate of hepatocytes and reaching the adjacent sinusoid, are divided into several perisinusoidal projections. Thus, the ZKI on average covers more than two adjacent sinusoids.

With liver damage, activation of the PCI and the process of fibrogenesis occurs, in which 3 phases are distinguished. They are designated initiation, prolongation and resolution (resolution of fibrous tissue). This process of transformation of “resting” HSCs into fibrosing myofibroblasts is initiated by cytokines (^-1,^-6,

Figure 4. - Perisinusoidal (subendothelial) and interhepatocellular processes (outgrowths) of the PCI

a - process of the PCI (yellow arrows) emerging from the cell body, uv. 30,000; b - extension of the ZCI, located along the surface of the sinusoidal capillary, containing a lipid droplet, uv. 30,000; c - subendothelially located processes of the PCI. Endothelial cell processes (pink arrows); d - interhepatocellular process of the PCI; area of destruction of the membranes of the HCI and hepatocyte (black arrows), uv. 10 000. Electron diffraction patterns

TOT-a), underoxidized metabolic products, reactive oxygen species, nitric oxide, endothelin, platelet-activating factor (PDGF), plasminogen activator, transforming growth factor (TGF-1), acetaldehyde and many others. Direct activators are hepatocytes in a state of oxidative stress, Kupffer cells, endotheliocytes, leukocytes, platelets producing cytokines (paracrine signals) and PCIs themselves (autocrine stimulation). Activation is accompanied by the expression (inclusion in work) of new genes, the synthesis of cytokines and proteins of the extracellular matrix (types I, III, U collagens).

At this stage, the process of activation of the PCI can be completed by stimulating the formation of anti-inflammatory cytokines in the PCI, inhibiting the production of TOT-a by macrophages in the damage area. As a result, the number of HCIs is sharply reduced, they undergo apoptosis and fibrosis processes in the liver do not develop.

In the second phase (prolonged), with prolonged constant paracrine and autocrine exposure to activating stimuli, the activated phenotype is “maintained” in the PCI, characterized by the transformation of the PCI into contractile myofibroblast-like cells that carry out the synthesis of extracellular fibrillar collagen.

The activated phenotype is characterized by proliferation, chemotaxis, contractility, loss of retinoid stores, and the formation of myofibroblast-like cells. Activated HSCs also show increased abundance of novel genes such as a-SMA, ICAM-1, chemokines, and cytokines. Cell activation indicates the onset of the early stages of fibrogenesis and precedes increased production of ECM proteins. The resulting fibrous tissue undergoes remodeling due to the breakdown of the matrix with the help of matrix metalloproteinases (MMPs). In turn, matrix breakdown is regulated by tissue inhibitors of matrixmetaloproteinases (TIMPs). MMPs and TIMPs are members of the zinc-dependent enzyme family. MMPs are synthesized in the HCI in the form of inactive proenzymes, which are activated upon cleavage of the propeptide, but are inhibited upon interaction with endogenous TIMPs - TIMPs-1 and TIMPs-2. HCIs produce 4 types of membrane-type MMPs, which are activated by IL-1β. Among MMPs, particular importance is attached to MMPs-9, a neutral matrix metalloproteinase that has activity against collagen type 4, which is part of the basement membrane, as well as against partially denatured collagen types 1 and 5.

The increase in the PCI population in various types of liver damage is judged by the activity of a significant number of mitogenic factors, related tyrosine kinase receptors and other identified mitogens that cause the most pronounced proliferation of PCI: endothelin-1, thrombin, FGF - fibroblast growth factor, PDGF - endothelial growth factor blood vessels, IGF - insulin-like growth factor. The accumulation of HCI in areas of liver damage occurs not only due to the proliferation of these cells, but also due to their directed migration into these areas through chemotaxis, with the participation of chemoattractants such as PDGF and leukocyte chemoattractant-MCP (monocyte chemotactic protein-1).

In activated HSCs, the number of lipid droplets is reduced to 1-3 with their location at opposite poles of the cell (Figure 5).

Activated HSCs acquire an elongated shape, significant areas of the cytoplasm are occupied by the Golgi complex, and quite numerous GRES cisterns (an indicator of protein synthesis for export) are revealed. The number of other organelles is reduced: few free ribosomes and polysomes, single mitochondria, and irregularly lysosomes are found (Figure 6).

In 2007, HSCs were first called liver stem cells, since they express one of the markers of hematopoietic mesenchymal stem cells - CD133.

Figure 5. - ZKI in the activated state

a, b - HCI (blue arrows) with single lipid inclusions localized at opposite poles of the nucleus. The perisinusoidal connective tissue (in Fig. 6a) and the intercellular matrix layer around the hepatocyte (in Fig. 6b) are colored red. Cytotoxic lymphocytes (purple arrows). Endothelial cell (white arrow). Close contact between a plasma cell (red arrow) and a hepatocyte. Semi-thin sections. The color of azure II is basic magenta. Microphotographs. Increased 1000 ; c, d - ultrastructural components of the HCI: mitochondria (orange arrows), Golgi complex (red arrow), cisternae of its more osmiophilic cis-side facing the expanded elements of the granular endoplasmic reticulum (green arrows), lysosome (blue arrow) (magnitude 10,000 and 20,000, respectively); c, d - electron diffraction patterns

Myofibroblasts, which are absent in the normal liver, have three potential sources: first, during intrauterine development of the liver, in the portal tracts, myofibroblasts surround the vessels and bile ducts during their maturation, and after full development of the liver, they disappear and are replaced in the portal tracts by portal fibroblasts; second, when the liver is damaged, they are formed due to portal mesenchymal cells and resting HCI, less often due to transitional epithelial-mesenchymal cells. They are characterized by the presence of CD45-, CD34-, Desmin+, glial fibrillary-associated protein (GFAP)+ and Thy-1+.

Recent studies have shown that hepatocytes, cholangiocytes and endothelial cells can become myofibroblasts through epithelial or endothelial to mesenchymal transition (EMT). These cells include markers such as CD45-, albumin+ (ie hepatocytes), CD45-, CK19+ (ie cholangiocytes) or Tie-2+ (endothelial cells).

Figure 6. - High fibrotic activity of HCI

a, b - myofibroblast (MFB), the cell contains a large nucleus, elements of the GRES (red arrows), numerous free ribosomes, polymorphic vesicles and granules, single mitochondria and a bright visualization sign - a bundle of actin filaments in the cytoplasm (yellow arrows); took away 12,000 and 40,000; c, d, e, f - high fibrotic activity of HCI while retinoid-containing lipid droplets are preserved in the cytoplasm. Numerous bundles of collagen fibrils (white arrows), retaining (a) and losing (d, e, f) specific transverse striations; took away 25 000, 15 000, 8 000, 15 000. Electron diffraction patterns

In addition, bone marrow cells, consisting of fibrocytes and circulating mesenchymal cells, can transform into myofibroblasts. These are CD45+ cells (fibrocytes), CD45+/- (circulating mesenchymal cells), collagen type 1+, CD11d+ and MHC class 11+ (Figure 7).

Literary data confirm not only the close connection between the proliferation of oval cells and the proliferation of sinusoidal cells, but also data on the possible differentiation of HCI into the hepatic epithelium, which was called mesenchymal-epithelial transformation of perisinusoidal cells.

In a state of fibrogenic activation, myofibroblast-like PCIs, along with a decrease in the number and subsequent disappearance of lipid droplets, are characterized by focal proliferation (Figure 8), immunohistochemical expression of fibroblast-like markers, including smooth muscle α-actin, and the formation of pericellular collagen fibrils in the spaces of Disse.

During the developmental phase of fibrosis, increasing hypoxia of the liver tissue becomes a factor for additional overexpression of pro-inflammatory adhesion molecules in stem cells - 1CAM-1, 1CAM-2, VEGF, proinflammatory

Interaction of hepatic ductal progenitor cells with liver myofibroblasts

Myofibroblast-like HSCs in a state of fibrogenic activation.

Figure 7. - Participants in myofibroblastic activation of PCI

lytic chemoattractants - M-CSF, MCP-1 (monocyte chemotactic protein-1) and SGS (cytokine-mediated neutrophil chemoattractant) and others that stimulate the formation of pro-inflammatory cytokines (TGF-b, PDGF, FGF, PAF, SCF, ET-1 ) and enhance the processes of fibrogenesis in the liver, creating conditions for the self-sustaining induction of continuous activation of the PCI and fibrogenesis processes.

On microscopic preparations, pericapillary fibrosis manifests itself in the form of intense red coloring of the perisinusoidal connective tissue and the intercellular matrix layer around hepatocytes (often dying). On electron microscopic preparations, fibrotic changes are visualized either in the form of formed large bundles of collagen fiber fibrils that have retained transverse striations, or in the form of massive

deposits in the Disse space of fibrous mass, which are swollen collagen fibers that have lost their periodic striations (Figure 9).

According to modern concepts, fibrosis is a dynamic process that can progress and regress (Figure 10).

Recently, several specific markers of PCI have been proposed: vitamin A (VA) bloom into lipid droplets, GFAP, p75 NGF receptor, and synaptophysin. Research is being conducted on the participation of liver HCI in the proliferation and differentiation of liver stem cells.

We studied the content of retinol-binding protein (RSB-4), which forms a complex with VA, the concentration of which in the blood plasma normally correlates with the body's supply of VA, 80% of which is found in the PCI.

A relationship has been established between the contents

Figure 8. - Focal proliferation of PCI in a state of fibrogenic activation

a - hyperplasia of the PCI (white arrows) in the lumen of the dilated sinusoids; b - proliferation of transdifferentiated HSC (white arrows), endothelial cell (pink arrow). Semi-thin sections. The color of azure II is basic magenta. Microphotographs. Increased 1000

Figure 9. - Final stage of myofibroblastic activation of the PCI

a, b - perisinusoidal fibrosis (white arrows). Peri-sinusoidal connective tissue and the intercellular matrix layer around hepatocytes (b) are stained with basic fuchsin red. HCIs activated and transformed into fibroblasts (blue arrows). Hz in Fig. a - hepatocyte with devastated cytoplasm. Semi-thin sections. The color of azure II is basic magenta. Microphotographs. Increased 1000; c, d - perisinusoidal and perihepatocellular fibrosis in the liver lobule, increased electron density of collagen fiber fibrils; condensation of the mitochondrial matrix in the hepatocyte (orange arrow). UV.8,000 and 15,000, respectively. Electron diffraction patterns

Table 1. - Indicators of RSB-4 content in patients with liver cirrhosis (LC) and chronic hepatitis (CH) of various etiologies, ng/ml (M±t)

Group n M±m р

Liver cirrhosis 17 23.6±2.29<0,05

CG, AST normal 16 36.9±2.05* >0.05

CG, AST >2 norms 13 33.0±3.04* >0.05

CG, ALT normal 13 37.5±3.02* >0.05

CG, ALT >2 norms 21 35.9±2.25* >0.05

Control 15 31.2±2.82

Note: p - significant differences with control (p<0,05); * - достоверные различия между ЦП и ХГ (р<0,05)

A false lobule surrounded by a fibrous septum. Masseau staining - circle of false lobule. Painting according to Nu.Uv.x50 Masson. UV.x200

Figure 10. - Dynamics of events in the false lobule of a patient with viral cirrhosis 6 months after transplantation of autologous mesenchymal stem cells into the liver

We eat RSB-4 and the 4th stage of fibrosis (cirrhosis), in contrast to chronic hepatitis, in which such a dependence was not observed, regardless of biochemical markers of inflammatory activity in the liver.

This fact must be taken into account when justifying replacement therapy to eliminate VA deficiency in the body, which may be due to the depletion of the potential of PCI caused by the progression of fibrosis in the liver.

1. The maximum effectiveness of assessing the structural and functional state of the PCI is ensured by a morphological study of an intravital biopsy with the simultaneous use of a set of cellular visualization techniques (light, electron microscopy of ultrathin sections and original methods of fixation and staining).

2. The results of a morphological study of PCI make it possible to improve the quality of intravital diagnosis of fibrosis, monitor it and predict the outcomes of chronic diffuse liver lesions at a higher modern level.

3. The results of morphological conclusions will allow the clinician to additionally include in the formulation of the final diagnosis updated data on the stage of chronicity (stabilization, progression or resolution of fibrosis) during therapy.

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CLINICAL CYTOLOGY OF THE LIVER: ITO STELLATE CELLS (HEPATIC STELLATE CELLS)

Tsyrkunov V. M., Andreev V. P., Kravchuk R. I., Kandratovich I. A. Educational Establishment "Grodno State Medical University", Grodno, Belarus

The aim of the work is to present the structural and functional characteristics of HSC based on the findings of cytological identification of intravital liver biopsy samples.

Materials and methods. Classical methods of light and electron microscopy of biopsy samples within the original technique of using ultrathin sections, fixation and staining were applied.

Results. The structural characteristics of the HSC of the liver biopsy samples from patients with chronic hepatitis C are presented on photo illustrations of light and electron microscopy. HSC are depicted at different stages (rest, activation) and during the process of transformation into myofibroblasts.

Conclusions. The use of original methods of clinical and morphological identification and evaluation of the functional status of HSC allows to improve the quality of diagnosis and prognosis of liver fibrosis.

Stellate cells. Liver fibrosis: past, present and future Portal triad and acinus

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annotation scientific article on fundamental medicine, author of the scientific work - Tsyrkunov V.M., Andreev V.P., Kravchuk R.I., Kondratovich I.A.

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