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The Role of Hyaluronic Acid and Versican in the Skin Extracellular Matrix Premio Accésit Congreso SIBB 2019

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The Role of Hyaluronic Acid and Versican in the Skin Extracellular Matrix Premio Accésit Congreso SIBB 2019 Biomecánica, Vol.27, 2019, pp 35-49 DOI: 10.5821/sibb.27.1.9279 The role of hyaluronic acid and versican in the skin extracellular matrix Premio Accésit Congreso SIBB 2019 J. González-Rico1*, C. Quílez1, V. López2, A. Muñoz-Barrutia1, J. L. Jorcano 1,2, D. Velasco1 1Department of Bioengineering and Aerospace engineering, Universidad Carlos III de Madrid, Leganés (Madrid), Spain 2 Regenerative Medicine Unit and Epithelial Biomedicine Division, CIEMAT, Madrid, Spain Abstract The extracellular matrix (ECM) is a structural network that comprises the bulk of the tissues. It acts as a supporting scaffold for the cells to develop their function and plays an active role in many processes such as proliferation and migration. Therefore, the ECM is an interesting object of study for regenerative medicine. In this article we make an extensive review of two key components of the ECM: the glycosaminoglycan Hyaluronic Acid (HA) and the proteoglycan Versican (Ver). These two molecules are present in the skin ECM and play active roles in processes such as differentiation, wound healing, hair follicle cycle and development. In our opinion, further biological insights in these two molecules and their interaction will be of great importance for skin tissue engineering applications. Keywords: Extracellular matrix, Glycosaminoglycans, Proteglycans, Hyaluronan, Versican Resumen La matriz extracelular (ECM, del inglés Extra-Cellular Matrix), es un entramado estructural que compone el grueso de los tejidos biológicos. Actúa como un andamiaje para el desarrollo de las células, y juega un papel activo en varios procesos biológicos tales como en la proliferación celular y la migración. Por ello, la matriz extracelular es un interesante objeto de estudio para la medicina regenerativa. En este artículo, realizaremos un análisis de dos componentes clave en la matriz extracelular: el glicosaminoglicano Ácido Hialurónico (HA, por sus siglas en ingles Hyaluronic Acid) y el proteoglicano Versicano (Ver). Estas dos moléculas están presentes en la matriz de la piel y toman roles activos en procesos como la diferenciación celular, la reparación y la cicatrización de las heridas y el desarrollo del ciclo del pelo. En nuestra opinión, un entendimiento mas detallado en estas dos moléculas y las interacciones que entre ellas se producen probará ser de gran importancia para el campo de la ingeniería de tejidos dedicada a la piel. Palabras clave: Matriz extracelular, Glicosaminoglicanos, Proteoglicanos, Ácido Hialuronico, Versicano Accronym list ECM – Extracellular Matrix Col – Collagen HA – Hyaluronic Acid HAS – Hyaluronan Synthase Ver – Versican HYAL – Hyaluronidase GAG – Glycosaminoglycan HABR – Hyaluronic Acid Binding Region PG - Proteoglycan EGF – Epithelial Growth Factor SC – Stratum Corneum CBP – Complement Binding Protein Correspondencia: Jorge González-Rico [email protected] 35 Introduction chains can vary widely, both among different GAG types and among chains of the same GAG The extracellular matrix (ECM) is a struc- type, the range of molecular weights in GAGs tural network made up of proteins, sacchari- is very broad, ranging from a few kiloDaltons des and other components. The ECM acts as to over a hundred kiloDaltons. Glycosamino- connective tissue, as well as a scaffold provi- glycans can be classified in sulfated and non- ding support to the cells. It was thought that sulfated GAGs. Sulfated GAGs are chondroitin the ECM was an inert, metabolically inactive sulfate, dermatan sulfate, keratan sulfate, hepa- substance and that its unique function was to rin and heparin sulfate, while hyaluronic acid provide structural support to the cells. Howe- or hyaluronan (HA) is the only non-sulfated ver, this vision of the ECM as a passive com- gag10. GAGs interact with numerous growth ponent in cellular activity has been debunked. factors, cytokines and chemokines11, cell sur- The view of the ECM as a mere tridimensio- face receptors and ECM molecules. GAGs par- nal (3D) scaffold was expanded with the disco- ticipate in many cell functions, such as signa- very that growth of most human cells depends ling, proliferation, migration, differentiation, on cellular adhesion to the ECM through a apoptosis and adhesion. mechanism called anchorage dependence. This Proteoglycans (PGs) can be classified de- mechanism allows cells to grow whenever they pending on their localization into four fami- are anchored to a surface or a scaffold1. lies: intracellular, cell surface, pericellular and The ECM is known to play an active role extracellular proteoglycans. Intracellular PGs in various cellular processes, such as prolifera- are solely composed by Serglycin, which is the tion, differentiation and migration2,3. It is for- only characterized PG present in secretory med by a variety of matrix macromolecules, compartments. Cell surface proteoglycans being the composition and structure of these are formed by two main subfamilies of PG, dependent on the tissue. which are syndecans and glypicans. Perice- llular membrane PGs carry mostly Heparan Components of the extracellular matrix Sulfate chains. As their name indicates they The main components of the ECM, re- are present in the surface of many cell types gardless of the tissue, are fibrous proteins and that anchor themselves via cell surface recep- proteoglycans (PGs)4. Fibrous proteins provi- tors such as integrins. They are also part of de structural support to the ECM. They form basement membranes. This family is formed three-dimensional structures that defines the by perlecan, agrin and collagen types XV and mechanical properties of the tissues in the di- XVIII. Finally, extracellular PGs form the lar- fferent organs. The most abundant fibrous pro- gest class, which is composed by two subfa- tein in the dermal ECM is the collagen, which is milies: hyalectans and small leucine-rich pro- in fact believed to be one of the most abundant teoglycans12. The family of the hyalectans is proteins in the whole animal kingdom5. Other formed by the PGs aggrecan, versican (Ver), fiber-forming proteins present in the ECM in- neurocan, and brevican, which share common clude fibronectin, vitronectin an elastin6,7. structural features. Their N- terminal contains Glycosaminoglycans (GAGs) are long, un- a HA-binding region, while the C-terminal branched polysaccharide chains. They usually domain binds to lectins. appear covalently bound to a protein core, for- ming proteoglycans. Glycosaminoglycans have Extracellular matrix of the skin a repeating disaccharide structure composed The skin is an organ composed by the fo- mainly of N-acetylated hexosamines (N-ace- llowing layers: epidermis, dermis and subcu- tyl-D-galactosamine or N-acetyl-D-glucosa- taneous fatty tissue. Each of the layers have mine) and D-/L-hexuronic acid (D-glucuronic different cell populations and performs diffe- acid or L-iduronic acid)8. GAGs are negati- rential functions (Figure 1). Naturally, in each vely-charged, which allows them to retain lar- of the skin layers, the composition and struc- ge amounts of water9. Since the length of GAG ture of the ECM is different. 36 Chondroitin sulfate Dermatan sulfate Sulfated GAGs Keratan sulfate Glycosaminoglycans Heparin GAGs Heparan sulfate Non-Sulfated GAGs Hyaluronic Acid Intracellular PGs Serglycin Syndecans Cell surface PGs Glypicans Perlecan Pericellular PGs Agrin Proteoglycans Collagen types XV PGs and XVIII Aggrecan Hyalectans Versican Neurocan Extracellular PGs Small leucine Brevican rich PGs Scheme 1. Representation of the skin and the components of its ECM. The dermis, the bulk of the skin, has a rich ECM mainly composed by collagen, elastin and HA (images adapted with permission from Servier Medical Art freeware image bank). - Lipids Epidermis - GAGs - Integrins Basal - Collagen Membrane - Elastin - GAGs Dermis (mainly HA) - Collagens Subcutaneous - Laminin fat tissue - Fibronectin Figure 1. Representation of the skin and the components of its ECM. The dermis, the bulk of the skin, has a rich ECM mainly composed by collagen, elastin and HA (images adapted with permission from Servier Medical Art freeware image bank). 37 Epidermis. In the epidermis, the cells are the elastic fibers16. highly packed. The keratinocytes and corneo- Subcutaneous fat tissue. The subcutaneous cytes (main cell population of the epidermis), tissue is largely composed of fat cells and is are closely linked to each other through des- often referred to as subcutaneous fat tissue or mosomes13. Therefore, the spaces between hypodermis. It is the layer between the dermis cells are narrow, and the scarce ECM is cons- and the fascia. The function of the subcuta- tricted to these spaces. The outermost layer of neous fat tissue is to provide thermal insula- the epidermis, the stratum corneum (SC) is tion, mechanical cushioning and store energy. where the cells are most packed, and the ECM, Additionally, fat cells or adipocytes also have which is almost non-existent, is mainly com- an endocrine function, secreting hormones posed by lipids. Ceramides, cholesterol, and such as leptin to alter energy turnover in the non-essential fatty acids in the stratum cor- body and to regulate appetite. Adipocytes also neum form lamellar layers, which composes have important signaling roles in osteogenesis its ECM14. As we move further down towards and angiogenesis, and physical functions like the basal membrane, the ECM becomes more phagocytosis. It has been reported that human abundant and includes proteins and GAGs fat contains multipotent stem cells20. such as
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