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Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization.
Clinical Research Center, University Hospital; Örebro Life Science Center, University Hospital Örebro, Örebro, Sweden.ORCID iD: 0000-0001-8304-2772
Department of Otolaryngology, University Hospital Örebro, Örebro, Sweden.
Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
Department of Surgical Sciences, Plastic Surgery Unit, Uppsala University, Uppsala, Sweden.
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2010 (English)In: Wound Repair and Regeneration, ISSN 1067-1927, E-ISSN 1524-475X, Vol. 18, no 5, 452-459 p.Article in journal (Refereed) Published
Abstract [en]

To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α-smooth muscle actin, was studied in a keratinocyte-fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor-β. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real-time polymerase chain reaction after removal of the epidermal layer. After 2 days of air-exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor-β. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α-smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.

Place, publisher, year, edition, pages
The Wound Healing Society , 2010. Vol. 18, no 5, 452-459 p.
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:oru:diva-48462DOI: 10.1111/j.1524-475X.2010.00605.xISI: 000282263500004PubMedID: 20731800Scopus ID: 2-s2.0-77956625499OAI: oai:DiVA.org:oru-48462DiVA: diva2:905470
Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2017-10-17Bibliographically approved
In thesis
1. Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
Open this publication in new window or tab >>Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. Reepithelialisation and epidermal wound coverage counteract excessive scar formation. We have previously shown that interleukin-1α (IL-1α) derived from keratinocytes conteracts TGF-β-stimulated CTGF-expression. The aim of this thesis was to further explore the effects of keratinocytes and IL-1α on gene and protein expression, as well as pathways, in TGF-β stimulated fibroblasts. Fibroblasts were studied in vitro by conventional two dimensional cell culture models and in a three dimensional keratinocyte-fibroblast organotypic skin culture model.

The results showed that IL-1 suppresses basal and TGF-β-induced CTGF mRNA and protein, involving a possible TAK1 mechanism. Keratinocytes regulate the expression of fibroblast genes important for the turnover of the extracellular matrix. Most of the genes analysed (11/13) were regulated by TGF-β and counter regulated by keratinocytes. The overall results support a view that keratinocytes regulate fibroblasts to act catabolically (anti-fibrotic) on the extracellular matrix.

Transcriptional microarray and gene set enrichment analysis showed that antagonizing effects of IL-1α on TGF-β were much more prominent than the synergistic effects. The most confident of these pathways was the interferon signaling, which were inhibited by TGF-β and activated by IL-1α. A proteomics study confirmed that IL-1α preferentially conteracts TGF-β effects. Six new fibroblast proteins involved in synthesis/ regulation were identified, being regulated by TGF-β and antagonized by IL-1α. Pathway analysis confirmed counter-regulation of interferon signaling by the two cytokines. These findings have implications for understanding the role of fibroblasts for inflammatory responses and development of fibrosis in the skin.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2016. 83 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 133
Keyword
Fibroblast, Keratinocyte, TGF-β, IL-1α, coculture, fibrosis CTGF/CNN 2, dermal, organotypic culture
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-48225 (URN)978-91-7529-120-8 (ISBN)
Public defence
2016-03-18, Universitetssjukhuset, Wilandersalen, Södra Grev Rosengatan, Örebro, 09:00 (English)
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Supervisors
Available from: 2016-02-12 Created: 2016-02-12 Last updated: 2017-10-17Bibliographically approved

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