[en] Hyaluronan (HA) is a glycosaminoglycan synthesized directly into the extracellular matrix by three hyaluronan synthases (HAS1, HAS2, and HAS3). HA is abundantly synthesized by keratinocytes but its epidermal functions remain unclear. We used culture models to grow human keratinocytes as autocrine monolayers or as reconstructed human epidermis (RHE) to assess HA synthesis and HAS expression levels during the course of keratinocyte differentiation. In both the models, epidermal differentiation downregulates HAS3 mRNA expression while increasing HAS1 without significant changes in hyaluronidase expression. HA production correlates with HAS1 mRNA expression level during normal differentiation. To investigate the regulation of HAS gene expression during inflammatory conditions linked to perturbed differentiation, lesional and non-lesional skin biopsies of atopic dermatitis (AD) patients were analyzed. HAS3 mRNA expression level increases in AD lesions compared with healthy and non-lesional skin. Simultaneously, HAS1 expression decreases. Heparin-binding EGF-like growth factor (HB-EGF) is upregulated in AD epidermis. An AD-like HAS expression pattern is observed in RHE incubated with HB-EGF. These results indicate that HAS1 is the main enzyme responsible for HA production by normal keratinocytes and thus, must be considered as an actor of normal keratinocyte differentiation. In contrast, HAS3 can be induced by HB-EGF and seems mainly involved in AD epidermis
Disciplines :
Dermatology
Author, co-author :
Malaisse, Jérémy; University of Namur > Research Unit of Molecular Physiology
Bourguignon, Virginie; University of Namur > Research Unit of Molecular Physiology
De Vuyst, Evelyne; University of Namur > Research Unit of Molecular Physiology
Lambert de Rouvroit, Catherine; University of Namur > Research Unit of Molecular Physiology
NIKKELS, Arjen ; Centre Hospitalier Universitaire de Liège - CHU > Dermatologie
Flamion, Bruno; University of Namur > Research Unit of Molecular Physiology
Poumay, Yves; University of Namur > Research Unit of Molecular Physiology
Language :
English
Title :
Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3
Publication date :
2014
Journal title :
Journal of Investigative Dermatology
ISSN :
0022-202X
eISSN :
1523-1747
Publisher :
Nature Publishing Group, New York, United States - New York
Bai KJ, Spicer AP, Mascarenhas MM et al. (2005) The role of hyaluronan synthase 3 in ventilator-induced lung injury. Am J Respir Crit Care Med 172:92-8
Barnes L, Carraux P, Saurat JH et al. (2012) Increased expression of CD44 and hyaluronate synthase 3 is associated with accumulation of hyaluronate in spongiotic epidermis. J Invest Dermatol 132:736-8
Bourguignon LY, Ramez M, Gilad E et al. (2006) Hyaluronan-CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis. J Invest Dermatol 126:1356-65
Camenisch TD, Spicer AP, Brehm-Gibson T et al. (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 106:349-60
Farwick M, Gauglitz G, Pavicic T et al. (2011) Fifty-kDa hyaluronic acid upregulates some epidermal genes without changing TNF-alpha expression in reconstituted epidermis. Skin Pharmacol Physiol 24:210-7
Frankart A, Malaisse J, De Vuyst E et al. (2012) Epidermal morphogenesis during progressive in vitro 3D reconstruction at the air-liquid interface. Exp Dermatol 21:871-5
Giltaire S, Herphelin F, Frankart A et al. (2009) The CYP26 inhibitor R115866 potentiates the effects of all-trans retinoic acid on cultured human epidermal keratinocytes. Br J Dermatol 160:505-13
Itano N, Sawai T, Yoshida M et al. (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274:25085-92
Jameson JM, Cauvi G, Sharp LL et al. (2005) Gammadelta T cell-induced hyaluronan production by epithelial cells regulates inflammation. J Exp Med 201:1269-79
Karvinen S, Pasonen-Seppanen S, Hyttinen JM et al. (2003) Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3. J Biol Chem 278:49495-504
Kaya G, Grand D, Hotz R et al. (2005) Upregulation of CD44 and hyaluronate synthases by topical retinoids in mouse skin. J Invest Dermatol 124:284-7
Kobayashi N, Miyoshi S, Mikami T et al. (2010) Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization. Cancer Res 70:7073-83
Lin W, Shuster S, Maibach HI et al. (1997) Patterns of hyaluronan staining are modified by fixation techniques. J Histochem Cytochem 45:1157-63
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402-8
Mack JA, Feldman RJ, Itano N et al. (2011) Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3. J Invest Dermatol 132:198-207
Mathay C, Giltaire S, Minner F et al. (2008) Heparin-binding EGF-like growth factor is induced by disruption of lipid rafts and oxidative stress in keratinocytes and participates in the epidermal response to cutaneous wounds. J Invest Dermatol 128:717-27
Mathay C, Pierre M, Pittelkow MR et al. (2011) Transcriptional profiling after lipid raft disruption in keratinocytes identifies critical mediators of atopic dermatitis pathways. J Invest Dermatol 131:46-58
Maytin EV, Chung HH, Seetharaman VM (2004) Hyaluronan participates in the epidermal response to disruption of the permeability barrier in vivo. Am J Pathol 165:1331-41
Meyer LJ, Stern R (1994) Age-dependent changes of hyaluronan in human skin. J Invest Dermatol 102:385-9
Minner F, Herphelin F, Poumay Y (2010) Study of epidermal differentiation in human keratinocytes cultured in autocrine conditions. Methods Mol Biol 585:71-82
Minner F, Poumay Y (2009) Candidate housekeeping genes require evaluation before their selection for studies of human epidermal keratinocytes. J Invest Dermatol 129:770-3
Monslow J, Sato N, Mack JA et al. (2009) Wounding-induced synthesis of hyaluronic acid in organotypic epidermal cultures requires the release of heparin-binding egf and activation of the EGFR. J Invest Dermatol 129:2046-58
Ohtani T, Memezawa A, Okuyama R et al. (2009) Increased hyaluronan production and decreased E-cadherin expression by cytokinestimulated keratinocytes lead to spongiosis formation. J Invest Dermatol 129:1412-20
Oyoshi MK, He R, Kumar L et al. (2009) Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol 102:135-226
Pasonen-Seppanen S, Karvinen S, Torronen K et al. (2003) EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: Correlations with epidermal proliferation and differentiation. J Invest Dermatol 120: 1038-44
Pasonen-Seppanen SM, Maytin EV, Torronen KJ et al. (2008) All-trans retinoic acid-induced hyaluronan production and hyperplasia are partly mediated by EGFR signaling in epidermal keratinocytes. J Invest Dermatol 128:797-807
Passi A, Sadeghi P, Kawamura H et al. (2004) Hyaluronan suppresses epidermal differentiation in organotypic cultures of rat keratinocytes. Exp Cell Res 296:123-34
Pienimaki JP, Rilla K, Fulop C et al. (2001) Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan. J Biol Chem 276: 20428-35
Poumay Y, Herphelin F, Smits P et al. (1999) High-cell-density phorbol ester and retinoic acid upregulate involucrin and downregulate suprabasal keratin 10 in autocrine cultures of human epidermal keratinocytes. Mol Cell Biol Res Commun 2:138-44
Rilla K, Oikari S, Jokela TA et al. (2013a) Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3. J Biol Chem 288:5973-83
Rilla K, Pasonen-Seppanen S, Deen AJ et al. (2013b) Hyaluronan production enhances shedding of plasma membrane-derived microvesicles. Exp Cell Res 319:2006-18
Rilla K, Pasonen-Seppanen S, Rieppo J et al. (2004) The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor. J Invest Dermatol 123:708-14
Rilla K, Siiskonen H, Spicer AP et al. (2005) Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity. J Biol Chem 280:31890-7
Rock K, Meusch M, Fuchs N et al. (2012) Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes. J Biol Chem 287:20056-69
Saavalainen K, Pasonen-Seppanen S, Dunlop TW et al. (2005) The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene. J Biol Chem 280:14636-44
Sayo T, Sugiyama Y, Takahashi Y et al. (2002) Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes. J Invest Dermatol 118:43-8
Siiskonen H, Karna R, Hyttinen JM et al. (2014) Hyaluronan synthase 1 (HAS1) produces a cytokine-and glucose-inducible, CD44-dependent cell surface coat. Exp Cell Res 320:153-63
Tammi R, Saamanen AM, Maibach HI et al. (1991) Degradation of newly synthesized high molecular mass hyaluronan in the epidermal and dermal compartments of human skin in organ culture. J Invest Dermatol 97:126-30
Toole BP (2004) Hyaluronan: From extracellular glue to pericellular cue. Nat Rev Cancer 4:528-39
Tran QT, Kennedy LH, Leon Carrion S et al. (2012) EGFR regulation of epidermal barrier function. Physiol Genomics 44:455-69
Tuhkanen AL, Tammi M, Pelttari A et al. (1998) Ultrastructural analysis of human epidermal CD44 reveals preferential distribution on plasma membrane domains facing the hyaluronan-rich matrix pouches. J Histochem Cytochem 46:241-8
Wells AF, Lundin A, Michaelsson G (1991) Histochemical localization of hyaluronan in psoriasis, allergic contact dermatitis and normal skin. Acta Derm Venereol 71:232-8
Yamada Y, Itano N, Hata K et al. (2004) Differential regulation by IL-1beta and EGF of expression of three different hyaluronan synthases in oral mucosal epithelial cells and fibroblasts and dermal fibroblasts: Quantitative analysis using real-time RT-PCR. J Invest Dermatol 122:631-9
