Disturbed Spatial WNT Activation-A Potential Driver of the Reticularized Skin Phenotype in Systemic Sclerosis

Area of Science:

• Dermatology and Molecular Biology
• Connective Tissue Diseases
• Skin Physiology

Background:

• Physiologic adult human skin integrity relies on poorly understood mechanisms.
• Systemic sclerosis (SSc) is characterized by skin fibrosis and structural changes.
• Understanding the molecular basis of SSc skin alterations is crucial for therapeutic development.

Purpose of the Study:

• To quantitatively compare the skin anatomy of SSc patients with controls.
• To investigate the underlying molecular mechanisms driving SSc-associated skin changes.
• To explore the role of WNT/β-catenin signaling in SSc skin.

Main Methods:

• Histological assessment of skin morphology in SSc patients, controls, and hypertrophic scar patients.
• Spatial analysis of WNT/β-catenin activation using RNAscope and immunofluorescence.
• Gene Ontology and gene set enrichment analysis to identify fibroblast subpopulations and marker genes.

Main Results:

• SSc skin displayed reduced papillae number, area, and height compared to controls.
• A shift towards a reticular expression profile of papillary/reticular marker genes was observed in SSc.
• Loss of normal spatial WNT/β-catenin activation polarization in SSc skin, with increased AXIN2 and β-catenin positive fibroblasts throughout the dermis.

Conclusions:

• The