Background/Purpose: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by vasculopathy and progressive fibrosis of the skin and internal organs. Individuals with SSc often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. However, the pathogenesis of esophageal dysmotility in SSc is poorly understood. Recently, studies have demonstrated that esophageal epithelial cells may play a more central role in the pathogenesis of SSc esophageal dysmotility than previously thought. In this study, we performed a thorough transcriptomic investigation of the SSc esophageal epithelium in humans to determine whether distinct molecular and cellular changes in esophageal epithelial cells contribute to impaired motility of the esophagus in SSc.

Methods: We performed single-cell RNA sequencing of paired proximal and distal esophageal mucosa biopsies from 10 individuals with SSc, 4 comparator individuals with gastroesophageal reflux disease (GERD), and 6 healthy controls (HCs), which yielded 230,720 esophageal epithelial cells across 39 samples following quality control. Esophageal motility was assessed using functional luminal imaging probe panometry combined with 4-dimensional high-resolution manometry.

Results: The proportion of epithelial cells in the outermost, superficial compartment of the esophageal epithelium was significantly reduced in SSc (9.4% vs 21.6% in HCs). Differential gene expression in SSc was primarily limited to the superficial compartment (3,572 genes vs. 232 in all other compartments), with significant upregulation of extracellular matrix and keratinization genes. These cellular and molecular changes in SSc were highly correlated with those seen in GERD, indicating they were secondary to reflux; however, their magnitudes were more pronounced in the proximal esophagus, suggesting that esophageal dysmotility leads to greater proximal acid exposure, which may contribute to aspiration. Genes that were most disproportionately dysregulated in SSc compared to GERD belonged to immune-related pathways, including innate and adaptive response, antigen presentation, and metal homeostasis, and may therefore point to pathogenic mechanisms.

Conclusion: By offering a comprehensive view of transcriptional dysregulation at single-cell resolution in human esophageal epithelial cells in SSc compared to GERD and healthy tissue, this work clarifies the state of epithelial cells in SSc-induced esophageal dysfunction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-esophageal-epithelium-in-systemic-sclerosis-cellular-and-molecular-dysregulation-revealed-by-single-cell-rna-sequencing/