CD44 Receptor Interactions

Figure 8.4 Proposed internalization pathway for hyaluronic acid-based nanoparticles loaded with plasmid The nanostructures interact with CD44 receptors in the plasma membrane, triggering the internalization of caveola vesicles that then fuse with the caveosome. The plasmid is release from the nanoparticles and finally is able to enter the nucleus.

With respect to hybrid hyaluronic acid nanoparticles, the high efficiency seen in the transfection process was due to the interaction of hyaluronic acid with CD44 receptors, as illustrated in Figure 8.7. The transfection effect seemed to last at least 10 days, reaching its maximum level on the fourth day after transfection of human corneal cells (HCE) and human conjunctiva cells (lOBA-NHC) [13,133]. This was evidenced by blocking (using an antibody or excess HA) these receptors, which led to a dramatic decrease in the transfection efficiency. 

HA is able to interact in an autocrine manner with its cell surface receptors that are located on the same cell, i.e. the cell is influenced by a product produced by this cell itself. For instance, it has been recently shown [113] that low-molar-mass HA induces the proteolytic cleavage of CD44 from the surface of tumor cells and promotes tumor cell migration significantly in this manner. 

De novo synthesized HA may be secreted from the cell and subsequently interact with different cell surface receptors, such as CD44, the receptor for HA-mediated motility (RHAMM), the HA receptor for endocytosis (HARE) and many others. It has become evident that these processes mediate at least three different, very important physiological processes signal transduction, formation of pericellular coats, and the receptor-mediated internalization. 

ECM is facilitated by small hyaluronic acid molecules implies a function in host defense, but has not been proven (106). Increased levels of hyaluronic acid were associated with colon inflammation, psoriasis, osteoarthritis, rheumatoid arthritis, and scleroderma (101,107,108), as well as with viral infections (109). Hyaluronic acid is produced by endothelial cells and binds to its receptor, CD44, expressed by activated T and B cells, inducing the attachment of the two cell types (110). This interaction is controlled by the expression of specific hyaluronic acids sub-types or by modifications of CD44 on platelets (111). High molecular weight hyaluronic acid and CD44 are essential for scarless embryonic wound repair (112). 

It is more likely that hyaluronic acid viscosupplementation produees its effects through down-regulation of aggrecanse-2, tumor necrosis factor alpha (TNF alpha), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases leading to anti-inflammatory, anabolic and analgesic effects, or through an interaction between hyaluronic acid and cell receptor CD44 [83, 95, 105, 113]. 

Unlike sulfated polysaccharides, some of the initial proof of HA s ability to interact with living cells came with the observation that hyaluronan accelerates cell growth. It has also been observed that hyaluronan initiates some cell aggregation. This was the first indication of a unique binding of the polysaccharide to the cell surface. Currently, several receptor proteins that bind to the surface of the HA cytoplasmic membrane have been isolated, including high-affinity receptor CD44 and receptor RHAMM (receptor for hyaluronan-mediated motility). 

Hyaluronan is widely used in applied biochemistry and enzymology as a substrate for the quantitative determination of the enzyme hyaluronidase. Scientific disputes about the possible relationship between HA and hyaluronate lyase and the pathogenicity of some streptococci are to be, as it seems, permanently carried out. Currently, much attention is paid to the study of the secondary and tertiary structures and dynamic conformation of HA in aqueous solutions and biological fluids the HA interaction with proteins, particularly receptor CD44 and other hyaladherins and the HA biocatalytic cleavage with different hyaluronidase the progression toward creating of recombinant strains and chimera products with the desired properties. 

CD44 could bind extracellular matrix ligands (primarily hyaluronan), which has an effect on cell behaviour regardless of their interaction with receptor tyrosine kinases, and the actin cytoskeletons can act as platforms for growth factors to participate in the function of the extracellular matrix (based on hyaluronan), in its assembly and dismantling. 

Hyaluronic acid Non-sulfated glycosaminoglycan found in the connective tissue. Strong interaction with endocytic receptors (such as CD44). FDA approved as injectable cosmetic device (wrinkle filler). [38-40]... 

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