Extracellular matrix as a regulator of cell behavior : Biological effects of hyaluronan biosynthesis and catabolism

Sammanfattning: Extracellular matrix surrounding cells is an important regulator of cellular functions. Hyaluronan (HA) is a glycosaminoglyean and a constituent component of the extracellular matrix in all tissues. It is synthesized by hyaluronan syntheses (HAS) at the inner surface of cell membrane and degraded by hyaluronidases to small fragments. HA regulates several biological functions and its metabolism is carefully regulated through the concerted action of HAS and HA-degrading enzymes. The aim of this thesis was to elucidate the biological role of HA fragments and hyaluronidases in angiogenesis and in irradiation-induced lung fibrosis in a rat experimental model. Low molecular weight HA fragments consisting of 6-20 monosaccharides stimulate angiogenesis both in vivo and in vitro. However, HA fragments of defined size, 12 monosaccharides (HA12), could also induce the differentiation of capillary endothelial cells (EC) into tube-like structures when cultured in collagen gel. Highly specific HA binding sites was identified on the surface of EC suggesting a receptor- mediated pathway for HA12 effect. Additional studies revealed that testicular hyaluronidase strongly stimulated the differentiation of EC. However, this effect was detectable with slower kinetics compared to that of basic fibroblast growth factor, a potent angiogenic factor. Interestingly, the ability of hyaluronidase to induce EC differentiation was mediated through the HA receptor CD44. HA is accumulated during the early phase of lung injury. Our studies on irradiated-induced rat lung injury revealed that the increased HA content was partly due to an up-regulation of rat HAS2 paralleled with decreased expression of rat hyaluronidase-2 (HYAL2) gene. In addition, a transient decrease of the expression of HA receptors on alveolar macrophages was observed. Furthermore, our results suggest that HA fragments produced by the action of hyaluronidases most likely promote the expression of types I and III collagen genes.