Index
They control many of the key functions in the liver, as well as their response to injuries.
There are 4 basic types of cells that reside in the liver:
- The hepatocyte
- The starry fat storage cell.
- The kupffer cell .
- The hepatic endothelial cell.
The challenge with the liver cells is that they feel lonely very fast, which makes them very temperamental when they are outside the body.
When the liver cells are removed from the body. The cells die immediately and the function is lost in an order of hours.
The researchers postulate that they can use liver cells to create new livers for more than 16,000 patients on the list of liver transplants, develop vaccines for hepatitis C and malaria and create better toxicity tests for new drugs, if only these liver cells they will cooperate.
Hepatocito
A hepatocyte (also called parenchymal cells) is a cell of the main parenchymal tissue of the liver. Hepatocytes constitute 70-85% of the cytoplasmic mass of the liver and participate in the synthesis of proteins, cholesterol, bile salts, fibrinogen, phospholipids and glycoproteins.
These cells are involved in:
- They are large polyhedral epithelial cells, with large central round nuclei (2 or more).
- Grouped in interconnected plates that are arranged in thousands of small polyhedral lobes.
- Store glucose in the form of glycogen, also vitamin b12, folic acid and iron.
- Participate in the billing and transport of lipids.
- Synthesize some of the plasma proteins (albumin, α and β globulins, prothrombin, fibrinogen).
- Metabolize / detoxify fat.
- Participate in the rotation of steroid hormones.
- Regulates cholesterol levels, cholesterol synthesis, bile salts and phospholipids
- Secretes bile (up to 1 liter per day).
- Protein synthesis.
- Protein storage.
- Transformation of carbohydrates.
- Detoxification, modification and excretion of exogenous and endogenous substances.
- Start of bile formation and secretion.
Structure
The typical hepatocyte is cubic with sides of 20-30 μm (in comparison, a human hair has a diameter of 17 to 180 μm). The typical volume of a hepatocyte is 3.4 x 10-9 cm3.
The smooth endoplasmic reticulum is abundant in the hepatocytes, while most of the cells in the body have small amounts.
Microanatomía
The hepatocytes show an eosinophilic cytoplasm that reflects numerous mitochondria and dotted basophil due to large amounts of rough endoplasmic reticulum and free ribosomes.
Brown lipofuscin granules (with increasing age) are also observed together with irregular areas of unstained cytoplasm; These correspond to glycogen and cytoplasmic lipid reserves during histological preparation. The average life of the hepatocyte is 5 months; they are able to regenerate.
The nuclei of the hepatocytes are round with scattered chromatin and prominent nucleoli.
Anisoroariasis (or variation in the size of the nuclei) is common and often reflects tetraploidy and other degrees of polyploidy, a normal feature of 30-40% of hepatocytes in adult human liver. Binucleated cells are also common.
The hepatocytes are organized in plates separated by vascular channels (sinusoids), an arrangement supported by a network of reticulin (collagen type III).
Hepatocyte plaques are one cell thick in mammals and two in chicken. The sinusoids show a discontinuous and fenestrated endothelial cell lining.
The endothelial cells do not have a basement membrane and are separated from the hepatocytes by the space of Disse, which drains the lymph into the lymphatic vessels of the portal tract.
Kupffer cells are scattered among endothelial cells; they are part of the reticuloendothelial system and the erythrocytes consumed by phagocytosis.
Stellate cells store vitamin A and produce extracellular matrix and collagen; They are also distributed among endothelial cells, but they are difficult to visualize by optical microscopy.
Function
Protein synthesis:
The hepatocyte is a cell in the body that makes serum albumin, fibrinogen, and the group of prothrombin clotting factors (except factors 3 and 4).
It is the main site for the synthesis of lipoproteins, ceruloplasmin, transferrin, complement and glycoproteins. Hepatocytes make their own structural proteins and intracellular enzymes.
Protein synthesis is performed by the rough endoplasmic reticulum (RER), and both the rough and smooth endoplasmic reticulum participate in the secretion of the proteins formed.
The endoplasmic reticulum (ER) is involved in the conjugation of proteins with lipid and carbohydrate residues synthesized by, or modified within, hepatocytes.
Metabolism of carbohydrates:
The liver forms fatty acids from carbohydrates and synthesizes triglycerides from fatty acids and glycerol. The hepatocytes also synthesize apoproteins with which they then assemble and export lipoproteins (VLDL, HDL).
The liver is also the main site in the body for gluconeogenesis, the formation of carbohydrates from precursors such as alanine, glycerol and oxaloacetate.
Lipid metabolism:
The liver receives many lipids from the systemic circulation and metabolizes the remains of chylomicrons. It also synthesizes acetate cholesterol and synthesizes bile salts even more. The liver is the only bile salt formation site.
Detoxification:
Hepatocytes have the ability to metabolize, detoxify and inactivate exogenous compounds such as drugs (drug metabolism) and insecticides and endogenous compounds such as steroids.
The drainage of intestinal venous blood to the liver requires an efficient detoxification of various absorbed substances to maintain homeostasis and protect the body against ingested toxins.
One of the detoxifying functions of hepatocytes is to modify the ammonia in urea for its excretion. The most abundant organelle in liver cells is the smooth endoplasmic reticulum.
Use in research:
Primary hepatocytes are commonly used in cell biology and biopharmaceutical research. Model in vitro systems based on hepatocytes have been of great help to better understand the role of hepatocytes in the physiological processes of the liver (patho).
In addition, the pharmaceutical industry has relied heavily on the use of hepatocytes in suspension or culture to explore the mechanisms of drug metabolism and even predict the metabolism of drugs in vivo.
For these purposes, hepatocytes are usually isolated from whole animal or human liver or liver tissue by digestion with collagenase, which is a two-step process.
In the first step, the liver is placed in an isotonic solution, in which calcium is removed to break the closed-cell junctions by the use of a calcium chelating agent.
Next, a solution containing collagenase is added to separate the hepatocytes from the hepatic stroma. This process creates a suspension of hepatocytes, which can be planted in multi-well plates and grown for many days or even weeks.
For optimal results, culture dishes should be first coated with an extracellular matrix (eg, collagen, Matrigel) to promote hepatocyte binding (typically within 1 to 3 hours after planting) and maintenance of the hepatic phenotype .
In addition, and overlapping with an extra layer of extracellular matrix is often performed to establish a sandwich culture of hepatocytes. The application of a sandwich configuration allows a prolonged maintenance of the hepatocytes in culture.
Freshly isolated hepatocytes that are not used immediately can be cryopreserved and stored. They do not proliferate in culture. Hepatocytes are intensely sensitive to damage during cryopreservation cycles, including freezing and thawing processes.
Even after the addition of classical cryoprotectants damage is still occurring while cryopreserved. However, recent cryopreservation and resuscitation protocols support the application of cryopreserved hepatocytes for most biopharmaceutical applications.
In other words, the hepatocytes ensure that our blood coagulates so we do not bleed to death, that cell communication is optimal and that we are able to transport fats into the bloodstream.
Other functions of hepatocytes include the transformation of carbohydrates (of alanine, glycerol and oxaloacetate), storage of proteins, initiation of the formation and secretion of bile and urea, and detoxification and excretion of substances.
Hepatic stellate fat storage cells
Think of hepatic stellate cells as the reserve army of the liver. Most of the time, this 5 to 8 percent of the liver cells simply sit in an inactive state, storing vitamin A and several important receptors.
The researchers believe that hepatic stellate cells play a key role in the release of scar tissue from collagen and promote liver healing.
- They reside very close to the hepatocyte (in the perisinusoidal space, not in the lumen).
- Store approximately 80% of the body’s supply of vitamin A and a variety of other lipids (under normal conditions).
- In conditions of liver injury, activated star cells respond to a large extent to pro-fibrogenic factors, such as transforming growth factor β (TGF-β).
- Proliferate in response to factors such as platelet-derived growth factor.
Kupffer Cells
In a way, kupffer cells are like bodyguards and killers of hepatocytes, protecting them from invaders and cell debris.
- Specialized crashed macrophages.
- Adhere to the sinusoidal endothelium (in the lumen of the sinusoid), mainly near the portal areas (= portal triads).
- Clean the blood of ingested bacterial pathogens that can enter the portal blood from the intestine.
- Eliminate aged erythrocytes and free heme for reuse.
- Act as antigen presenting cells in adaptive immunity.
- Cytokines and secret chemokines that recruit and expand the population of other proinflammatory cells in the liver.
Sinusoidal endothelial cells
Another type of liver cell is endothelial cells. Since they do not have tight membranes, these cells act as “scavengers” of nearby cells, collecting and circulating hepatocytes in the blood for example.
They are also primarily responsible for transporting white blood cells and other blood materials to the liver and for increasing the tolerance of the immune system to the liver.
They can absorb ligands, which serve as biological markers and drug binders. When stimulated, endothelial cells secrete cytokines, which is a form of cellular communication signal.
- Liver endothelial cells.
- It forms the wall of the blood vessels (sinusoids) that carry blood throughout the liver.
- They form a single layer with spaces between each cell known as a fenestra.
- They are rich in lysosomal enzymes necessary to degrade the endocycled material.
Hepatic cell cooperation in health and disease
The hepatic lobe is formed by parenchymal cells, that is, hepatocytes and nonparenchymal cells.
Unlike hepatocytes that occupy almost 80% of the total volume of the liver and perform most of the numerous liver functions, the non-parenchymal liver cells are located, which contribute only by 6.5% to the liver volume, but 40% to the total number of liver cells. in the sinusoidal compartment of the tissue.
The walls of the hepatic sinusoid are coated by three different cell types: sinusoidal endothelial cells (CES), Kupffer cells (CK) and hepatic stellate cells (HSC, formerly known as fat-storing cells, lipocytes, perisinusoidal cells or rich cells in vitamin A).
In addition, intrahepatic lymphocytes (LIH), which include pit cells, ie natural killer cells specific to the liver, are often present in sinusoidal light.
It has been increasingly recognized that in both normal and pathological conditions, many functions of hepatocytes are regulated by substances released from neighboring nonparenchymal cells.
The sinusoidal hepatic endothelial cells constitute the lining or wall of the hepatic sinusoid.
They perform an important function of filtration due to the presence of small fenestrations that allow the free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the surface of the hepatocytes.
Sinusoidal endothelial cells show a high endocytic capacity for many ligands, including glycoproteins, components of the extracellular matrix (ECM, such as hyaluronate, fragments of collagen, fibronectin or proteoglycan sulfate), immune complexes, transferrin and ceruloplasmin.
Sinusoidal endothelial cells can function as antigen-presenting cells (APCs) in the context of MHC-I and MHC-II restriction with the resultant development of antigen-specific T cell tolerance.
They are also active in the secretion of cytokines, eicosanoids (ie, prostanoids and leukotrienes), endothelin-1, nitric oxide and some components of the extracellular matrix.
Kupffer cells are tissue macrophages located intrasinusoidally with a pronounced endocytic and phagocytic capacity.
They are in constant contact with particulate materials derived from the intestine and soluble bacterial products, so that a subliminal level of their activation in the normal liver can be anticipated.
The hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha and other cytokines) and control the early phase of hepatic inflammation, playing an important role in the immune defense innate
The high exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators and, ultimately, liver damage.
The development of methods for the isolation and culture of the main types of liver cells allowed to demonstrate that both nonparenchymal and parenchymal cells secrete dozens of mediators that exert multiple paracrine and autocrine actions.
The experiments of cocultivation and the analysis of the effects of conditioned media in cultures of other types of liver cells have allowed the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes.
The key mediators involved in intercellular communication in the liver include prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF) and reagent species of oxygen (REO).
Paradoxically, the cooperation of the liver cells is better understood in some pathological conditions (ie, in experimental models of liver damage) than in the normal liver due to the possibility of comparing the cell phenotype in in vivo and in vitro conditions with the functions of the injured organ. .
The regulation of the metabolism of vitamin A provides an example of the physiological function of cellular intercommunication in the normal liver.
The majority (up to 80%) of total body vitamin A is stored in the liver as esters of long-chain fatty acids in the retina, which acts as the main source of retinoids used by all body tissues.
Hepatocytes are directly involved in the uptake of blood from chylomicron remnants and the synthesis of the retinol binding protein that transfers retinol to other tissues. However, more than 80% of hepatic retinoids are stored in lipid droplets of hepatic stellate cells.
Hepatic stellate cells are capable of absorbing and releasing retinol depending on the state of retinol in the body. It has been found that the activity of some major enzymes of the metabolism of vitamin A is many times greater by protein in the stellate cells than in the hepatocytes.
Despite advances in the understanding of the roles played by these two cell types in the metabolism of hepatic retinoids, the way in which retinoids move between parenchymal, stellate and blood plasma cells has not been fully elucidated .
Sinusoidal blood flow is, to a large extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin.
The main vasoactive substances that affect the constriction or relaxation of hepatic stellate cells derive from distant sources as well as neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins) and stellate cells (endothelin).
The cellular interference reflected by the adjusted modulation of the sinusoidal contraction is altered in pathological conditions, such as endotoxemia or hepatic fibrosis, through the excess synthesis of vasoregulatory compounds and the participation of additional mediators acting in a paracrine manner.
The liver is an important source of some growth factors and growth factor binding proteins. Although hepatocytes synthesize most of the insulin-like growth factor I (IGF-I), other types of non-parenchymal liver cells can also produce this peptide.
The cell-specific expression of different IGF binding proteins observed in rat liver and human liver provides the specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin and IGF-I, but also by the cytokines released by activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta).
Hepatic stellate cells can affect the turnover of hepatocytes through the synthesis of both positive and negative potent signals, such as, respectively, the hepatocyte growth factor or TGF-beta.
In addition to the typical activities of macrophages, Kupffer cells play an important role in the elimination of senescent and damaged erythrocytes.
Hepatic macrophages modulate immune responses through the presentation of antigens, suppression of T cell activation by antigen-presenting sinusoidal endothelial cells through paracrine actions of IL-10, prostanoids and TNF-alpha and participation in the development of oral tolerance to bacterial superantigens.
In addition, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that can damage hepatocytes and are active in the remodeling of the extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space.
They are characterized by the abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which encompass endothelial cells and provide focally a double coating for the sinusoid.
In normal liver, hepatic stellate cells store vitamin A, control extracellular matrix turnover and regulate the contractility of sinusoids.
Acute damage to hepatocytes activates the transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of the inflammatory fibrotic response.
Pit cells represent a liver-associated population of large granular lymphocytes, that is, natural killer cells. Spontaneously kill a variety of tumor cells in an unrestricted form of MHC, and this antitumor activity can be enhanced by the secretion of interferon gamma.
In addition to the pit cells, the adult liver contains other lymphocyte subpopulations such as gamma delta T cells, and “conventional” and “unconventional” alpha T cells, the latter containing natural killer T cells specific to the liver.
Although hepatocytes appear not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, it may contribute to its actions in the liver by intracellular activation of latent TGF-beta, and secretion of the biologically active isoform.
Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune complexes, anaphylatoxins and platelet activating factor, increase the production of glucose in the perfused liver, but they do not in isolated hepatocytes, acting indirectly through the prostaglandins released from the liver. the Kupffer cells.
In the liver, prostaglandins synthesized from arachidonic acid, mainly in Kupffer cells in response to various inflammatory stimuli, modulate the metabolism of hepatic glucose by increasing glycogenolysis in adjacent hepatocytes.
The release of glucose from glycogen supports the increased energy fuel demand by inflammatory cells such as leukocytes, and, in addition, allows improved glucose turnover in the sinusoidal endothelial cells and Kupffer cells that is necessary for effective defense of these cells against the invasion of microorganisms and oxidative stress in the liver.
Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictor, cholestatic and metabolic effects in the liver.
A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) works in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released in the extracellular space, acting paracrine in Kupffer and sinusoidal endothelial cells.
Therefore, hepatocytes are target cells by the action of eicosanoids and the site of their transformation and degradation, but they can not directly oxidize arachidonic acid to eicosanoids.
