Prostaglandin E₂ Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

Unchecked inflammation in Eosinophilic esophagitis (EoE) leads to esophageal fibrosis and eventual stricture. Differentiated fibroblasts, termed myofibroblasts, are the main effector cells in fibrosis, responsible for secreting extracellular matrix proteins leading to tissue stiffness. Regulating myofibroblasts has not been explored as a therapeutic possibility in the fibrostenotic esophagus. Herein, we aim to investigate the efficacy of Prostaglandin E₂ (PGE₂) in dedifferentiation of the EoE myofibroblast.

We evaluated the efficacy and mechanism of myofibroblast dedifferentiation using fetal esophageal fibroblasts (FEF3), patient-derived fibroblasts, and a murine model of EoE.

Fibrosis markers (αSMA, FN1, and COL1A1) and contractility of myofibroblasts were significantly decreased by PGE₂ via the cAMP pathway. PGE₂ treatment decreased nuclear accumulation of phospho-Smad2/3-YAP complex and induced phospho-YAP proteasomal degradation. Transcriptome analyses of FEF3 treated with TGFβ or PGE₂ revealed that the Integrin1 pathway, and specifically thrombospondin 1 (THBS-1), was significantly upregulated by TGFβ and downregulated by PGE₂, as supported by pseudo-bulk single-cell RNA-seq of EoE biopsies. THBS-1 was shown to be regulated by PGE₂ via the cAMP/YAP pathway, and its knockdown induced myofibroblasts dedifferentiation. In a murine model of EoE, Butaprost, agonist of the E-prostanoid G protein-coupled receptor 2, treatment significantly reduced the expression of THBS-1, αSMA, and FN1 along with a decrease in YAP nuclear translocation. Additionally, collagen fiber organization in the lamina propria was markedly reduced.

PGE₂ promotes dedifferentiation of myofibroblasts in EoE via the cAMP/YAP/THBS-1 pathway. Our data suggest that PGE₂ is a promising treatment strategy for EoE with stenosis.