CD44 receptors

Homof M, de la FM, Hallikainen M, Tammi RH, Urtti A (2008) Low molecular weight hyaluronan shielding of DNA/PEI polyplexes facilitates CD44 receptor mediated uptake in human corneal epithelial cells. J Gene Med 10 70-80... 

Wang, C., Tammi, M., and Tammi, R., Distribution of hyaluronan and its CD44 receptor in the epithelia of human skin appendages, Histochem., 98, 105, 1992. 

Model of inflammatory bowel disease in which cultured flat colonic smooth muscle cells were induced to secrete cables of hyaluronan (green) that bind to spheroidal mononuclear leukocytes via their CD44 receptors (red). Nuclei are stained blue. [Courtesy of... 

Slevin M, Krupinski J, Gaffney J, Matou S, West D, Delisser H, Savani RC, Kumar S. Hyaluronan-mediated angiogenesis in vascular disease uncovering RHAMM and CD44 receptor signahng pathways. Matrix Biol 2007 26 58-68. 

Grafting different bioactive components onto hyaluronan improves the stability of the complex. With assistance of the CD44 receptors, such complexes have ability of prolonged transportation into cells missing key metabolites using the endocytosis mechanism. 

The immune system is connected with HA [91-94], Hyaluronan is included into drugs used for the complex treatment of immunodeficient conditions associated with viral diseases. At the molecular level, the mechanism of action of the biopolymer is connected with the blocking of several molecular inflammation factors [93]. On the one hand hyaluronan activates inferonogenesis but on the other it increases action of the interferon inductor (e.g. double-stranded RNA) [91,92]. Interferon is produced mainly by the activated monocytes and T-cells of the immune system. The interleukins-2 and -5 (IL-2, IK-5) play a major role in the activation of T-cells that, in turn, activate synthesis of hyaluronan by endothelial capillary cells. Then hyaluronan stimulates synthesis of CD44 receptors, which is the key event for the activation of the lymphocytes and monocytes [93]. HA is used alone or in combination with interferon to slow down the development of the infection by the virus herpes simplex by application on the infected epithelium [61]. The obvious antimicrobial action of HA can be achieved by its cross-linking with hydrophilic polymers, which are capable of accelerated penetration through cell membranes or intercellular gaps [61]. 

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. 

The CD44 receptor was blocked with 1 pg of the monoclonal antibody Hermes-1 or with an excess of a HA/HAO mixture (50-fold with respect to the amount of HA in the nanostructures). The expressed P-galactosidase was quantified by the ONPG reaction (mean SD, n = 3). ( Significant difference, P < 0.05). Adapted with permission from [133],... 

Slevin, M., Krupinski, J., Gaffney, J., Matou, S., West, D., Dehsser, H., Savani, R. C., and Kumar, S. 2007. Hyaluronan-mediated angiogenesis in vascular disease UncoveringRhamm and Cd44 receptor signaling pathways. Matrix Biol, 26, 58-68. 

Figure 3.4 CD44 receptor levels in different types of cells, and the corresponding cell uptake, (a) Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast, liver and murine melanoma cells were treated with monoclonal antibody against CD44 receptors to determine the receptor levels on the surface of the cells by flow cytometry, (b) To demonstrate that the particles enter the cells via the receptors, MDA-MB468 cells were treated with HA-PEI/siRNA nanosystems at 50 nm for 12 h and observed under confocal microscope to capture images. The internalised Cy3-labelled-siRNA appears as red. (c) For competitive inhibition study, the cells were incubated with HA-PEI/Cy3-loaded-siRNA in the presence and absence of excess free soluble HA and observed under confocal microscope as shown. Reproduced with permission from S. Ganesh, A.K. Iyer, D.V. Morrissey and M.M. Amiji, Biomaterials, 2013, 34, 3489. 2013, Elsevier [19]...

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