Glycocalyx

What is the Glycocalyx?

The glycocalyx is a polysaccharide-based gel-like, highly hydrous cellular thin layer, covering present outside the cell. It acts as an interface between the extracellular matrix and cellular membrane. Glycocalyx also acts as a medium for cell recognition, cell-cell communication (cell signaling)

, and cell attachment. The literal meaning of glycocalyx is “sweet husk” where sweet implies carbohydrates and husk imply to extracellular material.

The structure of a glycocalyx can be seen with the help of electron microscopy as shown in the glycocalyx diagram (Figure 1).

 

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Glycocalyx Structure

The glycocalyx is a polysaccharide or carbohydrate-rich lining that envelopes the outer layer of a cell. The exact glycocalyx structure is still not known. However, biochemical analysis has revealed that components of the glycocalyx are proteoglycans, glycosaminoglycans, glycoproteins, and associated plasma proteins.

• Proteoglycans and Glycosaminoglycans

The proteoglycans are either loosely hanging or attached to a side chain of an unbranched carbohydrate through a bulky core (known as membrane-bound proteoglycans). These proteoglycans form the extracellular backbone of the glycocalyx.

The syndecans and glypicans are the primary proteoglycans of the glycocalyx.

1. Syndecans are transmembrane proteoglycans connected to the membrane via the membrane-spanning domain (syndecans).
2. Glypicans anchor to the membrane via glycosylphosphatidylinositol.

The glycocalyx core protein group of syndecans is 4 carbon and the proteoglycan core protein group of glypicans is 6 carbon. These two proteoglycans are attached to glycosaminoglycans (or GAGs) via a covalent bond through the protein core.  GAG chains that are attached to the proteoglycans include heparan sulfate, chondroitin sulfates, dermatan sulfates, keratin sulfates, and hyaluronan (or hyaluronic acid). Heparan sulfate is the most abundant GAGs in the glycocalyx (~50-90%) followed by chondroitin sulfate, and then hyaluronic acid.

Syndecans are attached to both the GAGs heparan sulfate and chondroitin sulfate. Conversely, glypicans are attached only to heparan sulfate. Hyaluronan does not bind to proteoglycans (rather, it interacts with the cell-membrane CD44). That’s because the hyaluronan is not charged unlike the sulfated GAGS, which are negatively charged. Nevertheless, hyaluronan can interact with the sulfated GAGs and help form and stabilize the gel-like structure of the glycocalyx.‌

• Glycoproteins

The glycoprotein component of the glycocalyx is responsible for cell adhesion. There are three cell adhesion molecules in the glycocalyx namely, the selectin family, the integrin family, and the immunoglobulin superfamily.

Depending upon the attachment of the glycan to the protein, the glycoprotein can be:

1. N-glycans, where glycan is attached to the asparagine side chain through nitrogen atom via N-glycosylation.
2. O-glycans, where glycan is attached to the oxygen atom of a serine or threonine side chain via O-glycosylation.

• Associated plasma proteins

Albumin, fibrinogen, fibronectin, and antithrombin are some of the proteins found in the glycocalyx.

Let’s learn more about them in the next section, glycocalyx in vascular endothelial tissue.

In Vascular Endothelial Tissue

The vascular endothelial glycocalyx is the specialized lining in the extracellular matrix that is present on the apical side of vascular endothelial cells (or the endothelial surface layer), protruding in the lumen of blood vessels (endothelial glycocalyx dimensions are ~aprox. 50–100 nm) (Figure 2).

The glycocalyx can be found in the majority of the vascular endothelial cells of arteries, veins, and microvessels (i.e., capillaries). The vascular endothelial cell membrane and glycocalyx are in a dynamic equilibrium with the blood flowing in the blood vessels and blood flow constantly affects the thickness and composition of glycocalyx to maintain homeostasis.

The non-circulating plasma also resides in the vascular endothelial layer glycocalyx (~1–1.7 L). The vascular endothelial glycocalyx carries a net negative charge.

The vascular endothelial glycocalyx is critical for plasma/blood and vascular homeostasis as it contains a wide range of hormones and enzymes that regulate the adherence of thrombocytes and leukocytes.

The primary enzymes found in the vascular endothelial membrane glycocalyx layer are:

• Growth factors
• Antithrombin-III
• Extracellular superoxide dismutase
• Endothelial nitric oxide synthase (endothelial NOS)
• Chemokines
• Angiotensin-converting enzyme
• Apolipoproteins

These enzymes help to maintain the glycocalyx intact to protect against any pathogen infection. The role of the glycocalyx in vascular endothelium is to act as a permeability vascular barrier and protect the vascular cellular walls from the flowing red blood cells in the vessels.

The vascular endothelial glycocalyx also prevents leukocyte adhesion and blood coagulation on the vascular walls. The vascular endothelial glycocalyx is also pertinent for filtering out the interstitial fluid from capillaries into the interstitial space.

Disruption and Disease

The glycocalyx is present around most of the body cells. The glycocalyx is a delicate lining and can be easily injured. However, the disruption can range from deterioration to destruction of the glycocalyx.

• Diabetes mellitus-induced vascular dysfunction

Disruption of glycocalyx has been found to result in diabetes mellitus-induced vascular dysfunction. Hyperglycemia has been found to result in the disruption of glycocalyx structure.

Increased blood levels of hyaluronic acid and coagulation activation along with a reduction in the thickness of glycocalyx (~50% reduction) have been observed in patients with hyperglycemia.

Disruption of the glycocalyx can affect the availability of nitrous oxide in the vascular system resulting in vasodilation. Thus, both acute hyperglycemia and chronic hyperglycemia can result in disruption of glycocalyx leading to the induction of vascular diseases and vascular complications or cardiovascular disorders (CVD) in diabetes.

Elevated levels of syndecan-1, chondroitin sulfate, and hyaluronic acid along with reduced levels of heparan sulfate are the biomarkers for the disruption of the glycocalyx in diabetes.

• Sepsis

The disruption of glycocalyx can result in the induction of sepsis, ischemic-reperfusion injury, and inflammation. Disruption of glycocalyx has been implicated in the severity of disease in dengue and the probability of septic shock in acute kidney injury.

Tumor necrosis factor-α (TNF-α) causes the disruption of the glycocalyx in sepsis. In sepsis, TNF-α induces the release of histamine, proteases, and heparinase that disrupts the glycocalyx. The breakdown of the glycocalyx results in the release of the exponentially high amount of the glycocalyx components like syndecan-1, heparan sulfate, etc into the blood which results in mortality or death in sepsis.

Disruption in the glycocalyx results in enhanced cardiac vascular permeability in sepsis, which leads to edema, loss of albumin, and fluid extravasation. Further, the breakdown of glycocalyx also increases the number of leukocytes and platelets that contributes to organ failures like respiratory failure and renal failure in sepsis.

• Atherosclerosis

Glycocalyx degradation has been found to result in the hardening of the blood vessels i.e., atherosclerosis. Atherosclerosis is one of the major causes of cardiac diseases and mortality caused due to endothelial dysfunction.

• Chronic kidney disease

In chronic kidney disease (CKD), an elevated amount of syndecan-1 and hyaluronan indicates the disruption of the glycocalyx.

In Bacteria and Nature

Beyond the bacterial cell wall, the majority of the bacterial cells possess glycocalyx. The type and composition of the bacteria glycocalyx however depend upon the bacterial strain. The glycocalyx and cell wall both act together to protect bacterial cells from an undesirable environment.

The bacterial glycocalyx or glycocalyx in prokaryotic cells varies according to the environment and type of bacteria. Accordingly, the two types of the glycocalyx in bacteria are (1) slime layer and (2) capsule.

1. Slime layer

   The slime layer is when the glycoprotein molecules of the glycocalyx are loosely bound to the bacterial cell wall. The slime layer protects the bacteria and also prevents it from dehydration & nutritional loss. The slime glycocalyx formed by the group or colony of the bacteria results in the formation of biofilms. Staphylococcus epidermidis is known to form biofilm over orthopedic medical devices. Such biofilms are highly resistant to antibiotics and can result in severe infection.

2. Capsule

   The capsule is where the glycocalyx is firmly attached to the bacterial cell wall and is sticky and gummy consistency. Capsule not only protects the bacteria but also provides an adhesion surface layer for the bacteria. The bacteria that possess capsules have the capacity to escape white blood cells or the immune cells of the human body and are thus pathogenic in nature. The adhesive property of the capsule also helps the bacteria to infect any cell and resist flushing out. Thus, the adhesive nature of the bacterial capsular glycocalyx is helpful in bacterial pathogenicity.

In the Digestive Tract

In the intestinal tract, on the apical side of the microvilli, a 0.3 μm thick mesh or glycocalyx can be found. Glycocalyces protrude outside the apical portion in the intestine on the intestinal luminal surface. Projecting from the apical portion of the microvilli, the intestinal glycocalyx, made up of acidic mucopolysaccharides and glycoproteins, helps in the absorption of nutrients and release of digestive enzymes for the breakdown of the food.

Other Generalized Functions

There are many critical functions played by glycocalyx in the plasma membrane, some of the main functions are as follows-

• Protection: One of the primary functions that glycocalyx plays is the protection of the cells. The glycocalyx is the gel-like cushioning around the cells that act as a barrier layer for the cells underneath. The glycocalyx act as a shield or gatekeeper that protects the cells from inflammatory stimuli, cytokines, reactive oxygen species, and enzymes during increased oxidative stress and inflammatory conditions as well as during cancer progression and bacterial infections.
• Cell adhesion: The glycocalyx, especially in bacteria, plays an important role in cell adhesion that eventually helps the bacteria to survive and establish in any environment like teeth, rocks, intestinal tract, skin, etc.
• Permeability: The glycocalyx also acts as a primary sieve that controls the material entering or coming in contact with the cell. The negative charge on the glycocalyx prevents the entry of negatively charged molecules into the cells due to the same charge repulsion. In fact, the glycocalyx is one of the primary factors that help to maintain strict permeability control in the blood-brain barrier (BBB).
• Cellular receptor: The glycolipids and glycoproteins in the glycocalyx act as cell surface receptors for certain molecules that help in their binding to the cells.
• Mechanotransducers: The glycocalyx has been found to be sensitive to the fluid shear stress caused due to mechanical forces like blood flow. Heparan sulfate and hyaluronan can detect and amplify the shear stress forces. The mechanotransduction feature of the glycocalyx helps modulate the release of nitric oxide (NO) in the blood vessels eventually helping in the maintenance of the coronary vascular bed, vascular wall tone, and structure
• Reproductive function: The glycocalyx has been found to play a role in egg fertilization by sperm and further zygotic development.

 

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References

• Costerton, J. W., Irvin, R. T., & Cheng, K. J. (1981). The bacterial glycocalyx in nature and disease. Annual Reviews in Microbiology, 35(1), 299-324.
• Möckl, L. (2020). The emerging role of the mammalian glycocalyx in functional membrane organization and immune system regulation. Frontiers in cell and developmental biology, 8, 253.
• Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A., & oude Egbrink, M. G. (2007). The endothelial glycocalyx: composition, functions, and visualization. Pflugers Archiv : European journal of physiology, 454(3), 345–359. https://doi.org/10.1007/s00424-007-0212-8
• Yilmaz, O., Afsar, B., Ortiz, A., & Kanbay, M. (2019). The role of endothelial glycocalyx in health and disease. Clinical kidney journal, 12(5), 611–619. https://doi.org/10.1093/ckj/sfz042
• Uchimido, R., Schmidt, E. P., & Shapiro, N. I. (2019). The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Critical Care, 23(1). https://doi.org/10.1186/s13054-018-2292-6‌

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