The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation

Vera Vorstandlechner, Maria Laggner, Dragan Copic, Katharina Klas, Martin Direder, Yiyan Chen, Bahar Golabi, Werner Haslik, Christine Radtke, Erwin Tschachler, Konrad Hötzenecker, Hendrik Jan Ankersmit () and Michael Mildner ()
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Vera Vorstandlechner: Medical University of Vienna
Maria Laggner: Medical University of Vienna
Dragan Copic: Medical University of Vienna
Katharina Klas: Medical University of Vienna
Martin Direder: Medical University of Vienna
Yiyan Chen: Medical University of Vienna
Bahar Golabi: Medical University of Vienna
Werner Haslik: Medical University of Vienna
Christine Radtke: Medical University of Vienna
Erwin Tschachler: Medical University of Vienna
Konrad Hötzenecker: Medical University of Vienna
Hendrik Jan Ankersmit: Medical University of Vienna
Michael Mildner: Medical University of Vienna

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFβ1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis.

Date: 2021
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DOI: 10.1038/s41467-021-26495-2

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