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

Objective: Little is known on the mechanisms necessary to maintain the physiologic adult human skin integrity. This study aims to quantitatively describe anatomic changes in systemic sclerosis (SSc)–skin compared with controls and investigate the underlying mechanisms. Methods: Skin morphology was histologically assessed in 23 patients with SSc, 18 controls, and 15 patients with hypertrophic scars. Spatial WNT/β-catenin-activation was analyzed by RNAscope and immunofluorescence staining. Enrichment of reticular marker genes in predefined fibroblast subpopulations was done using Gene Ontology (GO) enrichment and gene set enrichment analysis. Results: SSc skin showed a decrease in number (P < 0.0001/P = 0.0004), area (P < 0.0001), and height (P < 0.0001) of papillae compared with controls and hypertrophic scars, respectively. The expression of papillary/reticular marker genes shifted toward a reticular expression profile in SSc. On the level of previously defined fibroblast populations, the increase of reticular marker genes was particularly pronounced in the PI16+ and SFRP4+ populations (P < 0.0001, respectively). Mechanistically, the expression of the WNT/β-catenin target AXIN2 and the number of fibroblasts with nuclear β-catenin-staining-pattern increased in the papillary compared with the reticular dermis in healthy skin. This polarization was lost in SSc with a two-fold increase in β-catenin-positive fibroblasts and AXIN2-expressing fibroblasts throughout the dermis (P = 0.0095). Enrichment of genes related to WNT/β-catenin-regulation was found in the PI16+ population that also relocates from the reticular to the papillary dermis in SSc. Conclusion: We demonstrate an association of the “reticularized” skin phenotype in SSc with a profound loss of physiologic spatial WNT/β-catenin-activation. Rescuing the spatial WNT/β-catenin-activation might help restore the physiologic skin organization in future therapeutic approaches of fibrosing disorders.