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Neoepidermalization from human skin explant cultures is promoted by ligand-activated HER3 receptor
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-89157OAI: oai:DiVA.org:uu-89157DiVA: diva2:159463
Available from: 2004-01-01 Created: 2004-01-01Bibliographically approved
In thesis
1. Human Epidermal Growth Factor Receptors and Biological Effects of HER-directed Molecules on Skin Epithelialization
Open this publication in new window or tab >>Human Epidermal Growth Factor Receptors and Biological Effects of HER-directed Molecules on Skin Epithelialization
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human skin forms a biologically active barrier and maintains vital protective functions through continuous regeneration of cells within its outermost layer, the epidermis. In healthy skin, renewal of epithelial cells is a tightly regulated process in which the epidermal growth factor receptor (EGFR or HER1) and its various ligands are involved. The biological role of other EGFR family members (HER2–4) in normal and diseased human skin has gained less interest. The purpose of this work was to investigate the expression and contribution of different HERs in cultured epidermis and psoriatic skin.

Epidermal regeneration was studied by fluorescence imaging of a skin explant model exposed to anti-psoriatic drugs, HER ligands or HER-blocking molecules. EGFR, HER2 and HER3 were all markedly expressed with an in vivo-like immunostaining pattern in cultured neoepidermis, whereas only low amounts of HER4 were detected at protein and mRNA levels. Re-epithelialization was associated with receptor activation. Application of HER-selective tyrosine kinase inhibitors and monoclonal antibodies reduced the proliferative activity, receptor phosphorylation and radial outgrowth from normal skin explants. Similar anti-dynamic effects were obtained with HER kinase inhibition of neoepidermis generated from psoriatic skin. Among the HER receptors, EGFR seemed to be the dominant subtype during epithelialization in vitro although HER2 and HER3 were also involved. HER2 probably functioned as a co-receptor for the kinase-deficient HER3 in neoepidermis. In vivo, expression of HER4 mRNA was detected in normal and uninvolved psoriatic skin but was virtually absent in lesional skin, a potentially important finding for HER signalling in psoriasis.

This thesis demonstrates the utility of combined dynamic and biochemical analyses of re-epithelialization and highlights the role of EGFR and other HERs for epidermal growth. It also underscores the potential of HER-directed inhibition to control hyperproliferative states of the epidermis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 62 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 424
National Category
Dermatology and Venereal Diseases
urn:nbn:se:uu:diva-89154 (URN)978-91-554-7426-3 (ISBN)
Public defence
2009-03-20, Enghoffsalen, Akademiska Sjukhuset, Ingång 50, Uppsala, 09:15 (Swedish)
Available from: 2009-02-26 Created: 2004-01-01 Last updated: 2011-06-29Bibliographically approved

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