TGFbeta und Fibrose der Haut
TGFbeta and fibrosis of the skin
von Marie Lüders
Datum der mündl. Prüfung:2021-07-08
Erschienen:2021-06-29
Betreuer:Prof. Dr. Cornelia Seitz
Gutachter:Prof. Dr. Cornelia Seitz
Gutachter:Prof. Dr. Dörthe Katschinski
Dateien
Name:Promotion TGFb und Fibrose der Haut_Marie Lü...pdf
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Zusammenfassung
Englisch
Systemic sclerosis (SSc) is a fibrotic disease characterized by TGFβ-mediated differentiation of dermal fibroblasts to contractile myofibroblasts leading to accumulation of extracellular matrix proteins. Multiple studies indicate a trigger function of fibrotic keratinocytes. In fibrotic, mechanically modified tissue the cytoskeleton might hold regulatory functions. The central question of this work was the functional role of the fibrosis-associated, actin binding protein Sm22α in fibrotic keratinocytes. Analyses were performed in an in vitro model for keratinocytes under fibrotic conditions, which was confirmed by induction of TGFβ-downstream targets and a significant induction of fibrotic markers. In motility analyses TGFβ1-induced cell-scattering was observed, additionally EMT-markers presented a partial EMT. Further, live cell analyses revealed significant alterations in migration properties including the distance covered and the velocity. The actin cytoskeleton showed increased protein expression of F-Actin as well as increased bundling of Sm22α-associated actin filaments. For the first time, a significant TGFβ-mediated induction of Sm22α-expression was detected also in keratinocytes. However, siRNA-mediated Sm22α-knockdown didn´t alter cell morphology or fibrotic marker expression, neither in homeostatic nor in fibrotic conditions. Overall, all findings support a fibrotic activation of keratinocytes. Significant modifications in the actin cytoskeleton were detected and indicate a functional role of its components, for example on altered cell motility. While siRNA-knockdown of Sm22α didn´t influence the examined parameters, further studies in co-cultures might disclose effects on dermal fibroblasts through epidermal-dermal interactions. If a modification of the epidermal fibrotic reaction suppresses the myofibroblast activation, this will open up an innovative therapeutic approach for Systemic sclerosis.
Keywords: Systemic sclerosis; Fibrosis