Hyaluronan

The polysaccharide hyaluronan is a polysaccharide featuring repeats of a disaccharide motif but unlike GAG, hyaluronan is not sulfated and present other specificities. Firstly, it is not bound to any protein and is secreted as free polysaccharide. Secondly, hyaluronan is polymerized at the plasma membrane from its reducing end, thus resulting in its extrusion from the cell surface. The resulting polymers can reach more than 10’000 repeats of the disaccharide GlcNAc(b1-4)GlcA(b1-3). The high molecular weight and negative charges of hyaluronan confer hydrophilic gel-like properties similar to a viscous lubricant. The production of hyaluronan is not limited to vertebrates. In fact, several bacteria express hyaluronan as a capsular component and even some giant viruses express a hyaluronan synthase gene, yet of unknown function. The human genome includes three hyaluronan synthase (HAS) genes, which encode enzymes of different kinetic parameters and product size. The HAS2 gene is essential for mammalian development as shown by the severe cardiac and vascular malformations observed in Has2-knockout embryos, which die by mid-gestation. By contrast, mice lacking the Has1 or Has3 genes develop normally, are viable and fertile.

FIG: HYAL ELONGATION

Several proteoglycans like aggrecan and versican bind to hyaluronan through a so-called “link” protein, thereby creating huge multi-molecular complexes. The production of hyaluronan increases during inflammation. This contributes to enhanced cell adhesion partially through binding to the leukocytic protein CD44. The binding of CD44 to hyaluronan influences signaling cascades regulating cell proliferation and motility. Hyaluronan production is also increased during the maturation of oocytes preceding ovulation. The cumulus cells surrounding the oocyte secrete large amounts of hyaluronan, which remain associated to the oocyte after ovulation. Capacitated spermatozoa express a GPI-anchored hyaluronidase at the tip of their head, allowing them to dig their way through the thick layer of hyaluronan.

FIG: HYAL BINDING GEL

Hyaluronan secretion increases the viscosity of the matrix surrounding cells. Recently, a study showed that fibroblasts from naked mole rats secrete very high amounts of hyaluronan constitutively. In addition to its unique morphological features, the naked mole rat is a peculiar animal by many accounts. The naked mole rat shows an extreme longevity for rodents with a lifespan of about 30 years. Another peculiarity of the naked mole rat is its deficiency in substance P, the neurotransmitter mediating pain signals. Accordingly, the naked mole rat is insensitive to acid burns and capsaicin (chili pepper) exposure. The high levels of hyaluronan released in the extracellular matrix increases contact inhibition, which decreases cell proliferation. This phenomenon has been linked to the very low incidence of the naked mole rat for cancer. In fact, the thick hyaluronan layer prevents the formation of tumors even when cells overexpress oncogenes. The specificity of the resistance to tumor formation conferred by hyaluronan was confirmed by restoration of tumor growth when the enzyme hyaluronidase was overexpressed and when the hyaluronan synthase gene Has2 was silenced in tumor cells.