Fakhouri Sara Chenguiti, Zhu Honglin, Li Yi-Nan, Ronicke Moritz, Rigau Aleix Rius, Dees Clara, Konstantinidis Laura, Schmid Ralf, Matei Alexandru-Emil, Eckstein Markus, Geppert Carol, Ludolph Ingo, Kreuter Alexander, Sticherling Michael, Berking Carola, Horch Raymund E, Schett Georg, Distler Jörg H W, Bergmann Christina
Department of Internal Medicine 3 - Rheumatology and Clinical Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany, and Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany.
Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Arthritis Rheumatol. 2025 Jun;77(6):740-749. doi: 10.1002/art.43094. Epub 2025 Mar 11.
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.
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.
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.
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.
关于维持成年人生理皮肤完整性所需机制的了解甚少。本研究旨在定量描述系统性硬化症（SSc）皮肤与对照相比的解剖学变化，并探究其潜在机制。
对23例SSc患者、18例对照者和15例肥厚性瘢痕患者的皮肤形态进行组织学评估。通过RNAscope和免疫荧光染色分析空间WNT/β-连环蛋白激活情况。使用基因本体（GO）富集和基因集富集分析来确定在预定义的成纤维细胞亚群中网状标记基因的富集情况。
与对照者和肥厚性瘢痕相比，SSc皮肤的乳头数量（P < 0.0001/P = 0.0004）、面积（P < 0.0001）和高度（P < 0.0001）均减少。SSc中乳头/网状标记基因的表达向网状表达谱转变。在先前定义的成纤维细胞群体水平上，网状标记基因的增加在PI16+和SFRP4+群体中尤为明显（分别为P < 0.0001）。从机制上讲，与网状真皮相比，健康皮肤乳头中WNT/β-连环蛋白靶标AXIN2的表达以及具有核β-连环蛋白染色模式的成纤维细胞数量增加。在SSc中这种极化消失，整个真皮中β-连环蛋白阳性成纤维细胞和AXIN2表达成纤维细胞增加了两倍（P = 0.0095）。在PI16+群体中发现了与WNT/β-连环蛋白调节相关的基因富集，该群体在SSc中也从网状真皮重新分布到乳头真皮。
我们证明SSc中“网状化”皮肤表型与生理性空间WNT/β-连环蛋白激活的严重丧失有关。恢复空间WNT/β-连环蛋白激活可能有助于在未来纤维化疾病的治疗方法中恢复生理性皮肤组织。
