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• W2034305425 abstract "Hyaluronan, a major extracellular matrix component in the epidermis, has been shown to control keratinocyte proliferation and differentiation in vitro. We assayed hyaluronan and hyaluronan synthases (has1–3) in mouse epidermis during fetal development, postnatal life, and trauma reaction in vivo. Hyaluronan increased in the epidermis when keratinocytes started to stratify on day E15, remained high until birth, and then rapidly declined, with corresponding changes in the mRNA levels of has2 and has3. The hyaluronan in adult mouse epidermis mainly resided around the orifices of the hair follicles, and the overall concentration was about one order of magnitude lower than in adult human epidermis. In adult mice, epidermal trauma caused by tape stripping rapidly increased hyaluronan, leading to a 6-fold increase in epidermal hyaluronan on day 3 following trauma. The hyaluronan response was associated with a strong induction of has2 and has3 mRNA, slightly higher CD44 expression, and considerable epidermal hyperplasia. The data show that the pre- and postnatal fluctuations in epidermal hyaluronan content correlate with the expression levels of has2 and has3. Stimulated hyaluronan synthesis through upregulated has expression is an inherent feature of the keratinocyte activation triggered by tissue trauma, and presumably important for a proper healing response. Hyaluronan, a major extracellular matrix component in the epidermis, has been shown to control keratinocyte proliferation and differentiation in vitro. We assayed hyaluronan and hyaluronan synthases (has1–3) in mouse epidermis during fetal development, postnatal life, and trauma reaction in vivo. Hyaluronan increased in the epidermis when keratinocytes started to stratify on day E15, remained high until birth, and then rapidly declined, with corresponding changes in the mRNA levels of has2 and has3. The hyaluronan in adult mouse epidermis mainly resided around the orifices of the hair follicles, and the overall concentration was about one order of magnitude lower than in adult human epidermis. In adult mice, epidermal trauma caused by tape stripping rapidly increased hyaluronan, leading to a 6-fold increase in epidermal hyaluronan on day 3 following trauma. The hyaluronan response was associated with a strong induction of has2 and has3 mRNA, slightly higher CD44 expression, and considerable epidermal hyperplasia. The data show that the pre- and postnatal fluctuations in epidermal hyaluronan content correlate with the expression levels of has2 and has3. Stimulated hyaluronan synthesis through upregulated has expression is an inherent feature of the keratinocyte activation triggered by tissue trauma, and presumably important for a proper healing response. phosphate buffer phosphate-buffered saline Hyaluronan is a high molecular mass extracellular glycosaminoglycan expressed in most tissues (Fraser et al., 1997Fraser J. Laurent T. Laurent U. Hyaluronan: Its nature, distribution, functions and turnover.J Intern Med. 1997; 242: 27-33Crossref PubMed Scopus (1320) Google Scholar). It is especially enriched in matrices undergoing remodeling, e.g. during morphogenesis (Toole, 2001Toole B. Hyaluronan in morphogenesis.Semin Cell Dev Biol. 2001; 12: 79-87Crossref PubMed Scopus (405) Google Scholar; Camenisch et al., 2002Camenisch T. Schroeder J. Bradley J. Klewer S. McDonald J. Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors.Nat Med. 2002; 8: 850-855Crossref PubMed Scopus (262) Google Scholar), wound healing (Mack et al., 2003Mack J. Abramson S. Ben Y. et al.Hoxb13 knockout adult skin exhibits high levels of hyaluronan and enhanced wound healing.FASEB J. 2003; 17: 1352-1354Crossref PubMed Scopus (69) Google Scholar), or tumor growth (Toole, 2001Toole B. Hyaluronan in morphogenesis.Semin Cell Dev Biol. 2001; 12: 79-87Crossref PubMed Scopus (405) Google Scholar; Toole et al., 2002Toole B.P. Wight T.N. Tammi M.I. Hyaluronan–cell interactions in cancer and vascular disease.J Biol Chem. 2002; 277: 4593-4596Crossref PubMed Scopus (414) Google Scholar). Through its large hydrodynamic domain hyaluronan helps to form a soft matrix, thus facilitating cell detachment, migration, and proliferation (Toole, 2001Toole B. Hyaluronan in morphogenesis.Semin Cell Dev Biol. 2001; 12: 79-87Crossref PubMed Scopus (405) Google Scholar). In addition to these physicochemical effects, hyaluronan induces intracellular signals through binding to cell surface receptors, such as CD44 and RHAMM (Turley et al., 2002Turley E.A. Noble P.W. Bourguignon L.Y. Signaling properties of hyaluronan receptors.J Biol Chem. 2002; 277: 4589-4592Crossref PubMed Scopus (820) Google Scholar), thereby contributing to cellular processes like proliferation and migration. In human skin, large quantities of hyaluronan reside in the dermal connective tissue, but it can reach high local concentrations also in the epidermis (Tammi et al., 1989Tammi R. Ripellino J.A. Margolis R.U. Maibach H.I. Tammi M. Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture.J Invest Dermatol. 1989; 92: 326-332Crossref PubMed Scopus (117) Google Scholar). It is strongly expressed around the basal and spinous cells, whereas the terminally differentiated cells of stratum corneum usually lack hyaluronan (Tammi et al., 1988Tammi R. Ripellino J.A. Margolis R.U. Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe.J Invest Dermatol. 1988; 90: 412-414Abstract Full Text PDF PubMed Google Scholar; Wang et al., 1992Wang C. Tammi M. Tammi R. Distribution of hyaluronan and its CD44 receptor in the epithelia of human skin appendages.Histochemistry. 1992; 98: 105-112Crossref PubMed Scopus (123) Google Scholar). It has been suggested to support epidermal homeostasis by maintaining the extracellular space to facilitate the exchange of nutrients and waste products (Tammi et al., 1988Tammi R. Ripellino J.A. Margolis R.U. Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe.J Invest Dermatol. 1988; 90: 412-414Abstract Full Text PDF PubMed Google Scholar), but it may also have more direct effects on keratinocytes. Our experiments in vitro have shown that growth factors like epidermal growth factor (EGF) and keratinocyte growth factor (KGF), which stimulate keratinocyte migration and proliferation, also strongly upregulate hyaluronan synthesis (Pienimäki et al., 2001Pienimäki J.P. Rilla K. Fulop C. et al.Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan.J Biol Chem. 2001; 276: 20428-20435Crossref PubMed Scopus (157) Google Scholar; Karvinen et al., 2003Karvinen S. Pasonen-Seppanen S. Hyttinen J.M. et al.Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3.J Biol Chem. 2003; 278: 49495-49504Crossref PubMed Scopus (127) Google Scholar; Pasonen-Seppänen et al., 2003Pasonen-Seppänen S. Karvinen S. Törrönen K. et al.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. 2003; 120: 1038-1044Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), whereas factors, such as hydrocortisone (Ågren et al., 1995Ågren U.M. Tammi M. Tammi R. Hydrocortisone regulation of hyaluronan metabolism in human skin organ culture.J Cell Physiol. 1995; 164: 240-248Crossref PubMed Scopus (35) Google Scholar) and 4-methylumbelliferone (Rilla et al., 2004Rilla K. Pasonen-Seppänen S. Rieppo J. Tammi M. Tammi R. The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor.J Invest Dermatol. 2004; 123: 708-714Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), which downregulate hyaluronan synthesis, also slow down cell motility and proliferation. Moreover, transfected keratinocytes expressing an antisense has2 gene migrate at a slow rate in a scratch wound assay in vitro, and proliferate less than control cells (Rilla et al., 2002Rilla K. Lammi M.J. Sironen R. et al.Changed lamellipodial extension, adhesion plaques and migration in epidermal keratinocytes containing constitutively expressed sense and antisense hyaluronan synthase 2 (Has2) genes.J Cell Sci. 2002; 115: 3633-3643Crossref PubMed Scopus (57) Google Scholar). To establish an animal model for studies in vivo on the role of hyaluronan in the epidermis, we determined the hyaluronan content and distribution in fetal and adult mouse skin using histochemical and biochemical methods. We found that in normal adult mouse epidermis, the concentration of hyaluronan is considerably lower than in human epidermis, whereas both species show very similar hyaluronan content and distribution during the fetal period. But, strong epidermal hyaluronan staining was occasionally also seen in mice, mostly in hyperplastic skin areas with signs of tissue damage. This prompted us to study whether epidermal hyaluronan synthesis is upregulated after a trauma created by tape stripping in mouse epidermis. The results showed a rapid, several fold increase in epidermal hyaluronan content through upregulation of the hyaluronan synthases has2 and has3, and a subsequent decline correlating with the re-established epidermal integrity. Hyaluronan synthesis is thus an inherent feature of the epidermal keratinocyte activation in vivo, and has2 and has3 appear to be immediate targets of the signals that follow injury, and promote epithelial wound healing. Hyaluronan content in fetal mouse skin was studied using histochemical staining of hyaluronan. It was already found in the epidermis on day E13, when the epidermis is composed of two cell layers: the stratum germinativum and the periderm. Both of these cell types were hyaluronan positive (Figure 1a). Later, at E15, when stratification of the epidermis had started and the intermediate cell layers were formed, hyaluronan was found in all cell layers, i.e., around the basal, intermediate, and peridermal cells (Figure 1b). At E17, epidermal differentiation had proceeded, and granular and cornified cells were established (Figure 1c). Then hyaluronan disappeared from the superficial epidermis, both granular and cornified layers being almost devoid of hyaluronan, whereas basal and intermediate cell layers were intensely stained. This staining pattern also prevailed in newborn mouse epidermis (Figure 1d). The mesenchyme was moderately hyaluronan positive at the primitive stage E13 (Figure 1a), but showed increased staining by E15 (Figure 1b), and was very intensely positive by E17 (Figure 1c), and in newborn mice (Figure 1d). The immunohistochemical signal for CD44 was first detected in E15 fetuses in the epidermis from the facial areas whereas at E13 the epidermis was totally negative (Figure 1j). CD44 signal was upregulated by the epidermal stratification (Figure 1k), but was limited to the basal and spinous cells at the time of appearance of the granular and cornified layers (Figure 1l). In young mice (at the age of 4 wk), hyaluronan was found in the basal and spinous layers of epidermis (Figure 1e), but the staining intensity was markedly reduced as compared with that in the newborn animals (Figure 1d). In specimens taken at 2 mo or later, hyaluronan staining was typically low in the epidermis (Figure 1f). Hyaluronan, when found in young or adult animals, was present in the epidermal areas close to the hair infundibulum (Figure 1h), whereas the interfollicular epidermal areas contained less hyaluronan. Similar patterns were observed in skin samples taken from various anatomical locations, i.e. tail (Figure 1f), ear (Figure 1g), and back (data not shown). Epidermis from tail, however, usually showed more hyaluronan than epidermis from ear. To obtain an estimate of the magnitude of this variation, a visual scoring of hyaluronan staining in epidermis was carried out (Figure 2). In the newborn tail epidermis, staining of interfollicular epidermis (score 3) was seen in 76% of the specimens analyzed (Figure 2). By 1 mo the epidermal hyaluronan was already reduced so that only 17% and 38% of the tail and ear specimens, respectively, showed interfollicular signal (score 3), and at the age of 2–5 mo, 15% and 66% of samples from the epidermis of tail and ear, respectively, showed no signal at all (score 0) (Figure 2). Most of the samples taken at 7 mo had also very little hyaluronan, and it was just around follicles (80%–83% scored 0–1), but there were a few isolated areas with score 3 (Figure 2). The concentration of hyaluronan in the epidermis from different age groups was analyzed using an enzyme-linked sorbent assay (ELSA) assay (Table I). The rapid decline after birth confirmed the results of the histochemical analyses. The high hyaluronan content in the newborn mouse epidermis corresponded to that found previously in adult human epidermis (Tammi et al., 1989Tammi R. Ripellino J.A. Margolis R.U. Maibach H.I. Tammi M. Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture.J Invest Dermatol. 1989; 92: 326-332Crossref PubMed Scopus (117) Google Scholar), whereas the concentration was significantly lower (p<0.001) in the older age groups (from 1 mo on) (Table I).Table IAge-related changes of hyaluronan concentration in mouse epidermisNewborn1 mo2–5 mo>7 moHA (ng per mg)87±6 (5)24±5 (6)29±4 (40)28±9 (13)Epidermis was separated from dermis with a short ethylenediamine tetraaceticacid treatment and hyaluronan was measured with enzyme-linked sorbent assay as described in Materials and Methods. The newborn samples are from the whole body and the other age groups represent tail skin. The data show means±SE of the number of animals indicated in parentheses. p<0.001 between newborn animals and the older age groups (analysis of variance). Open table in a new tab Epidermis was separated from dermis with a short ethylenediamine tetraaceticacid treatment and hyaluronan was measured with enzyme-linked sorbent assay as described in Materials and Methods. The newborn samples are from the whole body and the other age groups represent tail skin. The data show means±SE of the number of animals indicated in parentheses. p<0.001 between newborn animals and the older age groups (analysis of variance). Staining for CD44 in the basal and lowest spinous cells of the fetal epidermis (Figure 1l) remained positive in adult mouse skin (Figure 1m). Hyaluronan staining of adult mouse specimens revealed occasional restricted areas with strong hyaluronan expression (Figure 1i). These sites also showed signs of tissue trauma (disrupted stratum corneum, inflammatory cells, epidermal hyperplasia), suggesting that epidermal hyaluronan expression is induced by trauma. To test the idea, epidermis in mouse tail was injured by removing stratum corneum and granular cell layers with repeated tape stripping (Figure 3a), and taking samples for histology and biochemical assays 1–10 d after the trauma. One day after stripping, the hyaluronan staining was clearly elevated at wound edge, whereas epidermis in the more severely damaged central area showed a lower hyaluronan signal (Figure 3a). The adjacent, non-traumatized epidermis and the hair follicles close by became hyaluronan positive at this time point (Figure 3b). The enhanced hyaluronan signal was even more striking 3 d after the stripping as seen in an overview of the skin area spanning the injured, adjacent, and more distant epidermis (Figure 3d), and in the high-power views from the corresponding specimens (Figure 3e–h). Hyaluronan was found in the reformed epidermis below the eschar (Figure 3d and e), where its intensity varied from modest in less regenerated neoepidermis (e) to intense in more fully regenerated neoepidermis (d). The adjacent, hyperplastic epidermis (∼200 μm from the traumatized area) showed strong staining intensity (Figure 3f and g), whereas the hyaluronan signal decreased with increasing distance from the trauma (Figure 3d, g, and h). This lateral hyaluronan expression reaction, with diminishing intensity by distance, was detectable on day 3 as far as 2 mm away from the edge of the stripped site. The hyaluronan staining was localized in the basal and spinous cells, mainly close to their plasma membranes, whereas the superficial vital cell layers and cornified cell layers remained negative (Figure 3f–h). The hyaluronan signal was very intense in the adjacent hair follicles, especially in the upper parts of the outer epidermal root sheaths, which also showed hyperplasia, (Figure 3c). By day 7, a strong epidermal hyaluronan staining was seen below the eschars. In the areas lateral to the trauma, however, hyaluronan staining had started to decline (Figure 3l). Interestingly, in these areas the spinous cells often remained hyaluronan positive whereas the basal cells showed less staining (Figure 3l). Stripping also caused an increased staining intensity of CD44 in the hyperplastic epidermal area, with more positive cell layers (Figure 3j) than in the areas more far away from the wound (Figure 3k). The keratinocytes in the neoepidermis were CD44 positive (Figure 3i), although their staining intensity was typically lower in the less regenerated areas than in the hyperplastic areas. In just 1 d after tape stripping, there was an almost 3-fold increase in the epidermal hyaluronan concentration, measured with the ELSA, and a 6-fold increase on day 3 (Figure 4a). The effect of tape stripping was statistically significant (p<0.001, analysis of variance). On day 7, when epidermal hyperplasia reached its maximum, hyaluronan still gave a strong histological signal in the epidermis (Figure 3l), but its concentration had already started to decline (Figure 4a). By day 10, the concentration of hyaluronan in the tape-stripped epidermis approached that in controls (Figure 4a). Total RNA was isolated from the epidermis of fetal (E18), newborn, and adult mice, and the levels of Has1, Has2, Has3, and CD44 mRNA were compared with that of glyceraldehyde phosphate dehydrogenase (GAPDH), using RT-PCR (Figure 4b). In the fetal (E18) and in the newborn mouse epidermis, both Has2 and Has3 were expressed. This was in a contrast to normal adult mouse epidermis, where in most samples the levels of all Has isoforms remained below the detection limit (Figure 4b), a finding in agreement with the minor hyaluronan concentrations in adult mouse epidermis, as shown above. The signal for Has1 was low or absent in epidermal samples of all age groups studied (data not shown). Expression of CD44 was evident in the epidermis of all age groups, but its mRNA level was slightly higher in the newborn as compared with older animals (Figure 4b). Analysis of the expression levels of the three Has isoforms in the epidermis of the tape-stripped animals showed that both Has2 and Has3 mRNA levels were upregulated (Figure 4b), the control epidermis showing no signal all. The CD44 mRNA was also slightly upregulated by tape stripping (Figure 4b), corresponding to the result in immunohistochemistry. Tape stripping did not enhance Has1 expression (data not shown). The data demonstrate that the content of hyaluronan in murine epidermis undergoes large regulatory changes during development and aging. Hyaluronan and its CD44 receptor are expressed from the early fetal period in the epidermis, but are clearly upregulated at the beginning of epidermal stratification and differentiation. A little later, with the start of mature cornification, both hyaluronan and CD44 disappear from the superficial, terminally differentiated cells. Mouse and human epidermis develop in a similar way up to this point, with a relatively strong hyaluronan expression in all vital keratinocyte layers (Ågren et al., 1997Ågren U.M. Tammi M. Ryynänen M. Tammi R. Developmentally programmed expression of hyaluronan in human skin and its appendages.J Invest Dermatol. 1997; 109: 219-224Crossref PubMed Scopus (30) Google Scholar). After birth, however, hyaluronan declines rapidly and markedly in mouse epidermis, whereas in humans a high level of hyaluronan is maintained throughout life (Tammi et al., 1989Tammi R. Ripellino J.A. Margolis R.U. Maibach H.I. Tammi M. Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture.J Invest Dermatol. 1989; 92: 326-332Crossref PubMed Scopus (117) Google Scholar). The concentration found in this study is very close to that reported for adult mouse epidermis using an HPLC assay (Sakai et al., 2000Sakai S. Yasuda R. Sayo T. Ishikawa O. Inoue S. Hyaluronan exists in the normal stratum corneum.J Invest Dermatol. 2000; 114: 1184-1187Crossref PubMed Scopus (86) Google Scholar), confirming the low postnatal concentration. The hairlessness of human skin, with a more frequent and severe exposure to environmental challenges, may not be the only reason for the higher level of hyaluronan in postnatal human epidermis. The idea of a species difference in the basal synthesis activity is supported by our unpublished data indicating that epidermal keratinocytes from human skin synthesize more hyaluronan also in vitro, as compared with those from a mouse or rat. The high level of hyaluronan in the newborn epidermis, and the subsequent decline, were obviously because of the corresponding changes in the expression of has2 and has3, whereas a significant has1 signal was not found, in contrast to an earlier report (Sugiyama et al., 1998Sugiyama Y. Shimada A. Sayo T. Sakai S. Inoue S. Putative hyaluronan synthase mRNA are expressed in mouse skin and TGF-beta upregulates their expression in cultured human skin cells.J Invest Dermatol. 1998; 110: 116-121Crossref PubMed Scopus (101) Google Scholar). It has been known for a long time that hyaluronan is abundant in the early granulation tissue of dermal wounds (Hansen et al., 1980Hansen T. Garbarsch C. Helin G. Helin P. Holund B. Kofod B. Lorenzen I. Proteoglycans, DNA, and RNA in rat granulation tissue, skin, and aorta. Biochemical and histological studies.Acta Pathol Microbiol Scand. 1980; 88: 143-150Google Scholar), and associates with scarless healing (Longaker et al., 1990Longaker M. Whitby D. Adzick N. et al.Studies in fetal wound healing. VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation.J Pediatr Surg. 1990; 25: 63-68Abstract Full Text PDF PubMed Scopus (276) Google Scholar). This study demonstrates that the wounding-induced upregulation of hyaluronan synthesis is not limited to mesenchymal cells, but is very prominent also in the epithelium. The discovery that epidermal injury upregulates the expression of has2 and has3 in keratinocytes, and causes a 6-fold increase of epidermal hyaluronan, suggests that epidermal hyaluronan synthesis has an important role in the re-epithelialization, which involves migration of keratinocytes from the adjacent epidermis and the hair follicles within and close to the injury area. Recently, HOXB13 knockout mice were shown to exhibit elevated hyaluronan content both in the dermis and epidermis, and an enhanced rate of wound healing (Mack et al., 2003Mack J. Abramson S. Ben Y. et al.Hoxb13 knockout adult skin exhibits high levels of hyaluronan and enhanced wound healing.FASEB J. 2003; 17: 1352-1354Crossref PubMed Scopus (69) Google Scholar). Furthermore, application of acetone on mouse skin causes a minor trauma, but sufficient for epidermal barrier disruption, and also increases epidermal hyaluronan in vivo (Maytin et al., 2004Maytin E.V. Chung H.H. Seetharaman V.M. Hyaluronan participates in the epidermal response to disruption of the permeability barrier in vivo.Am J Pathol. 2004; 165: 1331-1341Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Previous studies have demonstrated that keratinocyte migration is retarded in an in vitro wound healing assay by blocking has2 gene expression (Rilla et al., 2002Rilla K. Lammi M.J. Sironen R. et al.Changed lamellipodial extension, adhesion plaques and migration in epidermal keratinocytes containing constitutively expressed sense and antisense hyaluronan synthase 2 (Has2) genes.J Cell Sci. 2002; 115: 3633-3643Crossref PubMed Scopus (57) Google Scholar), and the same effect comes with the hyaluronan synthesis inhibitor 4-methylumbelliferone (Rilla et al., 2004Rilla K. Pasonen-Seppänen S. Rieppo J. Tammi M. Tammi R. The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor.J Invest Dermatol. 2004; 123: 708-714Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Altogether, it is now obvious that hyaluronan synthesis enhances keratinocyte migration and epidermal wound healing. Hyaluronan accumulation in the epidermis may also influence the recruitment and function of inflammatory cells (de la Motte et al., 2003de la Motte C.A. Hascall V.C. Drazba J. Bandyopadhyay S.K. Strong S.A. Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: Inter-alpha-trypsin inhibitor is crucial to structure and function.Am J Pathol. 2003; 163: 121-133Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar), a necessary step in the wound healing process (Martin, 1997Martin P. Wound healing—aiming for perfect skin regeneration.Science. 1997; 276: 75-81Crossref PubMed Scopus (3426) Google Scholar). The keratinocytes in adult mouse epidermis, originally almost negative for hyaluronan, turned positive already during the first 24 h after the trauma. The rapid increase of hyaluronan suggests that has belong to the primary targets for the mediators of wound reaction. The fact that EGF increases keratinocyte has2 expression in less than 2 h (Pienimäki et al., 2001Pienimäki J.P. Rilla K. Fulop C. et al.Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan.J Biol Chem. 2001; 276: 20428-20435Crossref PubMed Scopus (157) Google Scholar) is in line with the idea that autocrine/paracrine agents like HB-EGF, released upon trauma, are responsible (Martin, 1997Martin P. Wound healing—aiming for perfect skin regeneration.Science. 1997; 276: 75-81Crossref PubMed Scopus (3426) Google Scholar). We have recently shown that the Has2 promoter in human keratinocytes has a functional response element for the transcription factor stat3, which, in turn, is activated by EGF. 1Saavalainen et al, submitted for publication. The expression of epidermal has2 is also rapidly upregulated by KGF, another important paracrine stimulator of epidermal wound healing, synthesized by the dermal cells (Karvinen et al., 2003Karvinen S. Pasonen-Seppanen S. Hyttinen J.M. et al.Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3.J Biol Chem. 2003; 278: 49495-49504Crossref PubMed Scopus (127) Google Scholar). There are thus established autocrine- and paracrine-signaling systems that may account for the observed induction of has expression and hyaluronan synthesis following skin trauma. The most intense hyaluronan signal eventually developed in the epidermal areas with strongest tissue hyperplasia, suggesting that hyaluronan is associated with rapid cell proliferation. In general, factors that increase epidermal hyaluronan also increase epidermal thickness (Karvinen et al., 2003Karvinen S. Pasonen-Seppanen S. Hyttinen J.M. et al.Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3.J Biol Chem. 2003; 278: 49495-49504Crossref PubMed Scopus (127) Google Scholar; Pasonen-Seppänen et al., 2003Pasonen-Seppänen S. Karvinen S. Törrönen K. et al.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. 2003; 120: 1038-1044Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), whereas antisense has2 transfection and an inhibitor of hyaluronan synthesis tend to inhibit proliferation and hyperplasia (Rilla et al., 2002Rilla K. Lammi M.J. Sironen R. et al.Changed lamellipodial extension, adhesion plaques and migration in epidermal keratinocytes containing constitutively expressed sense and antisense hyaluronan synthase 2 (Has2) genes.J Cell Sci. 2002; 115: 3633-3643Crossref PubMed Scopus (57) Google Scholar,Rilla et al., 2004Rilla K. Pasonen-Seppänen S. Rieppo J. Tammi M. Tammi R. The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor.J Invest Dermatol. 2004; 123: 708-714Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Hyaluronan may support epidermal hyperplasia by forming a loose matrix for the changes in cell shape that occur during mitosis, promoting cell displacement from the basal to the superficial layers, and facilitating diffusion of nutrients to the thickened epidermis. But, hyaluronan may also stimulate cell proliferation more directly, since cells overexpressing has2 show increased progression from G1 to S phase (Itano et al., 2002Itano N. Atsumi F. Sawai T. et al.Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell" @default.
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• W2034305425 title "Hyaluronan Synthase Induction and Hyaluronan Accumulation in Mouse Epidermis Following Skin Injury" @default.
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• W2034305425 doi "https://doi.org/10.1111/j.0022-202x.2005.23697.x" @default.
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