Eosinophilic esophagitis drives tissue fibroblast regenerative programs toward pathologic dysfunction.

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Pathologic tissue remodeling, scarring, and rigidity are hallmarks of inflammatory, autoimmune, and allergic diseases.
• Eosinophilic esophagitis (EoE) involves tissue remodeling, leading to dysphagia and esophageal strictures, yet underlying molecular mechanisms are unclear.
• Fibroblast dysfunction is implicated in EoE-associated tissue remodeling.

Purpose of the Study:

• To investigate the hypothesis that chronic EoE inflammation induces pathogenic fibroblasts with impaired tissue regeneration and motility.
• To elucidate the molecular mechanisms driving fibroblast dysfunction in EoE.

Main Methods:

• Single-cell RNA sequencing to analyze transcriptional profiles of EoE and healthy fibroblasts.
• Fluorescence-activated cell sorting (FACS) and functional assays to assess fibroblast differentiation, migration, and CD73 activity.
• In vivo and in vitro experiments to induce and rescue EoE fibroblast dysfunctions.

Main Results:

• EoE fibroblasts exhibit proinflammatory and pro-rigidity transcriptional programs, retaining chondrocyte-like differentiation but losing adipocyte-like capacity.
• EoE fibroblasts show increased migration and decreased CD73 expression and activity, indicating aberrant extracellular adenosine triphosphate handling.
• EoE fibroblast dysfunction can be recapitulated in healthy fibroblasts by reducing CD73 activity and reversed by adenosine repletion.

Conclusions:

• Chronic EoE inflammation drives pathogenic fibroblast phenotypes characterized by altered tissue regeneration and motility.
• Perturbed extracellular adenosine triphosphate handling and CD73 activity are key mechanisms in EoE fibroblast dysfunction.
• Modulating adenosine triphosphate handling and CD73 offers a potential therapeutic strategy for improving tissue regeneration in EoE and other type 2 inflammatory diseases.