Artikel
Disturbed spatial activation of WNT/β-catenin signaling in Systemic Sclerosis
Suche in Medline nach
Autoren
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Christina Bergmann
- University Hospital Erlangen, Erlangen
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Sara Chenguiti Fakhouri
- University Hospital Erlangen, Erlangen
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Laura Konstantinidis
- University Hospital Erlangen, Erlangen
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Honglin Zhu
- Xiangya Hospital, Changsha
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Aleix Rigaz
- University Hospital Erlangen, Erlangen
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Andrea-Hermina Györfi
- University Hospital Düsseldorf, Düsseldorf
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Markus Eckstein
- University Hospital Erlangen, Erlangen
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Carol-Immanuel Geppert
- University Hospital Erlangen, Erlangen
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Clara Dees
- University Hospital Erlangen, Erlangen
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Alexander Kreuter
- University Hospital Erlangen, Erlangen
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Michael Sticherling
- University Hospital Erlangen, Erlangen
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Georg Schett
- University Hospital Erlangen, Erlangen
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Jörg Distler
- University Hospital Düsseldorf, Düsseldorf
| Veröffentlicht: | 30. August 2023 |
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Gliederung
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Introduction: The structure of the dermis in Systemic Sclerosis (SSc) is disrupted and papillary structures of the upper dermal layer disappear. Little is known on mechanisms necessary to maintain the physiological adult human skin morphology. Here, we tested the hypothesis that aberrant activation of canonical WNT/β-catenin signaling in SSc is associated with a loss of spatial WNT/β-catenin gradients and whether these disturbances in WNT/β-catenin gradients correlate with the disturbed skin morphology in human SSc.
Methods: Dermal skin morphology was quantitatively assessed using HE and trichrome staining of skin sections of 40 SSc patients and 18 healthy controls. Spatial WNT/β-catenin activation was analyzed by RNAscope-in situ hybridization detection of AXIN2 and the distribution of nuclear β-catenin expression using immunofluorescence staining.
Results: The skin of SSc patients demonstrates a “reticularized” phenotype with decreased number, area and height of papillary structures compared to controls and shifts in the expression of papillary/reticular genes towards reticular markers. In skin sections of hypertrophic scars the papillary structure is preserved underlining that the loss of the papillary skin structures particularly occurs in SSc. In healthy skin, WNT3A-regulated target genes are enriched in papillary gene sets and the expression of AXIN2 and the number of fibroblasts with nuclear accumulation of β-catenin is increased in the papillary dermis compared to the reticular dermis. This polarization is lost in SSc skin, with a 2-fold increase in β-catenin-positive fibroblasts throughout the dermis and complete loss of the spatial gradient in AXIN2 expression. Confocal imaging revealed that the distribution of fibroblasts with nuclear accumulation of β-catenin is reversed in SSc skin with higher numbers in the reticular dermis compared to the papillary dermis.
Conclusion: Our study demonstrates profound “reticularization” of SSc skin and demonstrates an association of this phenotype with a profound loss of the physiological spatial WNT/β-catenin signaling gradient. Restoration of the spatial gradient of WNT/β-catenin signaling might thus help to store the physiological organization of the dermis in SSc patients.
