Insights into the pathogenesis of systemic sclerosis based on the gene expression profile of progenitor‐derived endothelial cells

Abstract

To determine the gene expression profile of endothelial cells derived from the endothelial progenitor cells (EPCs) of patients with systemic sclerosis (SSc). Microarray experiments were performed on Affymetrix GeneChip Human Exon 1.0 ST Arrays in unstimulated and hypoxia-stimulated EPC-derived cells from patients with SSc and control subjects. Followup of the raised hypotheses was performed ex vivo by immunohistochemical analysis of skin tissue. Signals from 92 probe sets and 188 probe sets were different in unstimulated and hypoxia-stimulated cells, respectively, from patients with SSc compared with controls. Within the largest groups of genes related to cell-cell interaction and vascular remodeling, down-regulation of tumor necrosis factor ligand superfamily member 10 (TNFSF10) and homeobox A9 (HOX-A9) was confirmed by real-time polymerase chain reaction and Western blots in EPC-derived cells and by immunohistochemistry in SSc skin tissue. Signals from 221 and 307 probe sets were different in unstimulated and hypoxia-stimulated cells, respectively, from patients with diffuse cutaneous SSc compared with patients with limited cutaneous SSc. Within the largest group of genes related to the inflammatory response, differential expression of TNFα-induced protein 3 and prostaglandin-endoperoxide synthase 2 was observed in EPC-derived cells and skin tissue from patients with SSc. Our data revealed important gene expression changes in EPC-derived endothelial cells from patients with SSc, characterized by a proadhesive, proinflammatory, and activated phenotype. Differential expression in lesional SSc skin tissue of new targets, such as TNF family members and HOX-A9, may contribute to the pathogenesis of SSc and deserves more in-depth exploration.