Hyaluronan and morphogenesis

Abstract

In the past decade, there has been an explosion of interest in hyaluronan, an often misunderstood, biochemically simple, yet functionally complex carbohydrate polymer that is a resident of many extracellular matrices. Previously thought of as a passive, space-filling component of the extracellular matrix, the so-called "goo" concept, hyaluronan has risen to a much higher regard in recent years, even being called "magic glue" in a recent perspective. Hyaluronan is likely to be the common thread in many morphogenetic processes, including condensation events and epithelial-to-mesenchymal transformation. Hyaluronan is comparatively unique as a component of the extracellular matrix as it is solely composed of carbohydrate. In order to truly understand this biopolymer, one must first understand its biosynthesis, then understand its uptake and turnover, then identify its binding proteins and receptors. Major advances have been made in all of these arenas within the past decade. Hyaluronan synthases, hyaluronidases, and the hyaladherins have been molecularly identified and cloned. Furthermore, many have now been inactivated, employing gene targeting strategies, to create mice deficient in the respective gene product function. Collectively, huge strides have been made in our understanding of the diverse biological functions for this fascinating molecule. Hyaluronan appeared in metazoans immediately prior to the arrival of the vertebrates, and may be required for the differentiation, development, and/or function of most cell lineages, structures, and tissues that we associate with vertebrates, such as the neural crest, the skeleton, including the teeth, skin, and hair, and the chambered heart. In this review, we will update the reader on the advances of the past decade and provide insight into those morphogenetic processes through which hyaluronan regulates vertebrate development.

Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns

“…In terms of in vitro enzymatic activity, Has3 is able to polymerize low molecular mass HA (Յ 2 ϫ 10 5 Da) rather than mostly high molecular mass HA (Ͼ 1 ϫ 10 6 Da) as observed for Has1 and Has2 (Spicer and McDonald, 1998). HA synthesis can be regulated by many growth factors and cytokines, including transforming growth factor-beta/ bone morphogenetic protein superfamily members, interleukin-1 beta, tumor necrosis factor-alpha, epidermal growth factor, and keratinocyte growth factor, depending on the cell types (Spicer and Tien, 2004). Regulation of HA synthesis by means of the HA synthases differs between cell types in part because given cell types express distinct profiles of one or more Has genes.…”

“…Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that is important during development and morphogenesis (Toole, 2001;Spicer and Tien, 2004). Initially discovered in the vitreous humor of the eye, this linear polymer of repeating units of D-glucuronic acid and N-acetylglucosamine can be found in virtually every tissue and body fluid of vertebrates (Laurent, 1998).…”

“…In general, lower concentrations of HA are able to promote aggregation, whereas higher concentrations have the reverse effect, separating cells from one another or from its substratum (Underhill and Toole, 1981;Green et al, 1988;Toole, 1991). As a molecule that closely associates with cells and has the ability to bind to multiple extracellular proteins, HA is an effective support structure in the extracellular matrix, particularly in supporting tissues of vertebrates, including cartilage, skin, smooth muscle, and other connective tissues (Spicer and Tien, 2004). As a signaling molecule, HA is able to activate several pathways through binding of HA receptors such as CD44 and receptor for hyaluronanmediated motility (RHAMM; Bourguignon et al, 2000;Lee and Spicer, 2000;Lokeshwar and Selzer, 2000;Oliferenko et al, 2000;Slevin et al, 2002).…”

Proliferation and cornification during development of the mammalian epidermis

“…In support of this hypothesis, we and others have shown that Hoxb13, which is first expressed in E13.5 epidermis, is upregulated in keratinocytes that have been induced to differentiate (Komuves et al, 2003;Mack et al, 2005). Hoxb13 knockout epidermis shows significantly higher levels of hyaluronan (Mack et al, 2003), a molecule that is thought to promote cellular proliferation and inhibit differentiation (reviewed in Spicer and Tien, 2004). In addition, forced expression of Hoxb13 in a rat epidermal organotypic model significantly reduces the number of proliferating cells in the basal layer and drives terminal differentiation, as evidenced by a dramatically thickened cornified layer (Fig.…”

Recent Applications of Polymeric Biomaterials and Stem Cells in Tissue Engineering and Regenerative Medicine

“…20 Among these, the linear glycosaminoglycan hyaluronic acid (HA), which is composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine, is widely distributed in the ECM and critical to vertebrate tissue morphogenesis. 21 HA has been approved for use in clinic both as viscous fluid and sheet formulations, and HA is indicated for knee pain and surgical adhesions, respectively. Many large clinical trials have confirmed the effectiveness of HA for these applications.…”