Dipeptidylpeptidase-4-mediated fibronectin interaction promotes deposition of a profibrotic extracellular matrix

Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is a skin blistering disease associated with progressive, severe dermal fibrosis. RDEB was employed as a pro-fibrotic model to study the role of fibrillin microfibrils and the contribution of fibroblast subpopulations in this process. Fibrillins were studied since they are key structural components in the dermis and they have been described to contribute to fibrosis.
The fibrillin microfibril deposition and arrangement was altered in RDEB skin. The changes were replicated in 3D-skin equivalents as wells as in standard 2D-cell culture. The altered fibrillin microfibril deposition and arrangement was well in line with changes in fibronectin deposition and fiber arrangement. Since fibronectin is a prerequisite for fibrillin deposition, the changes in microfibril architecture were considered a consequence of changes in fibronectin deposition and organization.
To explain altered ECM deposition, RDEB fibroblasts were used as a model of pro-fibrotic fibroblasts to subsequently study the role of different fibroblast subpopulations or states in the pathogenic process of fibrosis. Dysregulation of fibroblast phenotypes, including progressive increase of pro-fibrotic DPP4-positive fibroblasts, was identified to occur in RDEB during the evolution of fibrosis in human and mice. DPP4 inhibitors normalized the altered deposition of fibronectin and subsequently fibrillin microfibrils. Although DPP4 directly interacted with fibronectin, DPP4-regulated fibronectin deposition was rather dependent on DPP4-mediated maturation of the fibronectin N-terminus. DPP4-mediated fibronectin maturation led to a delayed and dysregulated fibronectin deposition.
This study provides mechanistic insights to the observed pro-fibrotic effects of DPP4 and extends the understanding of fibronectin and fibrillin microfibril assembly in health and disease

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2024

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2024
• Urheber: Zeyer, Karina
• Beteiligte Personen und Organisationen: Bruckner-Tuderman, Leena ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/256872
• URN: urn:nbn:de:bsz:25-freidok-2568727
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 15.08.2025, 07:36 MESZ