• English
  • Deutsch
  • Log In
    or
  • Research Outputs
  • Projects
  • Researchers
  • Institutes
  • Statistics
Repository logo
Fraunhofer-Gesellschaft
  1. Home
  2. Fraunhofer-Gesellschaft
  3. Artikel
  4. Vascularized Three-Dimensional Models of Human Skin Fibrosis
 
  • Details
  • Full
Options
2020
  • Zeitschriftenaufsatz

Titel

Vascularized Three-Dimensional Models of Human Skin Fibrosis

Abstract
Background: The complex pathophysiological processes that result in fibrotic tissue remodeling in systemic sclerosis involve interplay between multiple cell types (1). Experimental models of fibrosis are essential to provide a conceptual understanding of the pathogenesis of these diseases and to test antifibrotic drugs. Current models of fibrosis have important limitations: the in vivo models rely on species that are phylogenetically distant, whereas the in vitro models are oversimplified cultures of a single cell type in an artificial two-dimensional environment of excessive stiffness, which imposes an unphysiological cell polarization (2). Objectives: Here we evaluated the potential use of vascularized, three-dimensional in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs. Methods: Skin equivalents were generated by seeding human endothelial cells, fibroblasts and keratinocytes on a decellularized porcine extracellular matrix with perfusable vascular structure. The skin models were cultured for one month in a system that ensured perfusion of the vascular network at physiological pressure. Fibrotic transformation induced by TGFv and response to nintedanib as an established antifibrotic drug was evaluated by capillary Western immunoassays, qPCR, histology and immunostaining. Results: The vascularized human skin equivalents formed the major skin structures relevant for the pathogenesis of fibrosis: a polarized, fully matured epidermis, a stratified dermis and a perfused vessel system with small capillaries. Exposure to TGFv led to the fibrotic transformation of the skin equivalents, with activated TGFv downstream pathways, increased fibroblast-to-myofibroblast transition and excessive deposition of extracellular matrix. Treatment of models exposed to TGFv with nintedanib (a drug with proven antifibrotic effects) ameliorated the fibrotic transformation of skin equivalents with reduced TGFv signaling, fibroblast-to-myofibroblast transition and decreased extracellular matrix deposition. Conclusion: Here we describe a novel in vitro model of skin fibrosis. Our data show that vascularized skin equivalents can reproduce all skin layers affected by fibrosis, that, upon exposure to TGFv, these models recapitulate key features of fibrotic skin and that these skin models can be used as a platform for evaluation of antifibrotic drugs in a setting with high relevance for human disease.
Author(s)
Matei, A.E.
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Chen, C.W.
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Kiesewetter, L.
Fraunhofer-Institut für Silicatforschung ISC
Györfi, A.H.
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Li, Y.N
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Trinh-Minh, T.
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Kuppevelt, T. van
Radboud Institute for Molecular Life Sciences, Department of Biochemistry, Radboud University Medical Center, Nijmegen, Netherlands
Hansmann, J.
Fraunhofer-Institut für Silicatforschung ISC
Juengel, A.
Center of Experimental Rheumatology, University Hospital Zurich/Zurich Center of Integrative Human Physiology (ZIHP), Zürich, Switzerland;
Schett, G
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Groeber-Becker, F.
Fraunhofer-Institut für Silicatforschung ISC
Distler, J.
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany;
Zeitschrift
Annals of the rheumatic diseases
Konferenz
Annual European Congress of Rheumatology (EULAR) 2020
Thumbnail Image
DOI
10.1136/annrheumdis-2020-eular.3141
Language
Englisch
google-scholar
ISC
Tags
  • fibrotic tissue remod...

  • multiple cell types

  • models of fibrosis

  • antifibrotic drugs

  • skin structures

  • Cookie settings
  • Imprint
  • Privacy policy
  • Api
  • Send Feedback
© 2022