Association of endothelial to mesenchymal transition and cellular senescence with fibrosis in skin biopsies of systemic sclerosis patients: a cross-sectional study

Yu Hsiang Chiu, Julia Spierings, Jacob M. van Laar, Jeska K. de Vries-Bouwstra, Marijke van Dijk, Roel Goldschmeding

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly understood. Methods We performed a cross-sectional study on archival skin biopsies from 18 SSc patients and four controls. Dermal fibrosis and inflammatory cell infiltration were scored in HE and Masson's Trichrome-stained sections. The presence of senescence was defined by P21 and/or P16 positivity in Ki-67 negative cells. Endothelial to mesenchymal transition (EndMT) was identified by co-localisation of CD31 and α-SMA in immunofluorescent double-stained sections, and by an enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm in immunohistochemical double staining. Results The histological dermal fibrosis score of SSc skin biopsies was correlated with the modified Rodnan skin score (rho 0.55, p=0.042). Staining for markers of cellular senescence on fibroblasts was correlated with fibrosis score, inflammatory score, and CCN2 staining on fibroblasts. Moreover, EndMT was more abundant in skin from patients with SSc (p<0.01) but did not differ between groups with different fibrosis severity. The frequency of these EndMT features increased with the abundance of senescence markers and CCN2 on fibroblasts and dermal inflammation. Conclusion EndMT and fibroblast senescence were more abundant in skin biopsies from SSc patients. This finding indicates that both senescence and EndMT are involved in the pathway leading to skin fibrosis and might be valuable biomarkers and/or possible targets for novel therapeutic interventions.

Original languageEnglish
Pages (from-to)1612-1617
Number of pages6
JournalClinical and Experimental Rheumatology
Volume41
Issue number8
Early online date9 Jun 2023
DOIs
Publication statusPublished - 1 Aug 2023

Keywords

  • cellular senescence
  • connective tissue diseases
  • fibrosis
  • scleroderma
  • systemic sclerosis

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