Suprabasal cells retain progenitor cell identity programs in eosinophilic esophagitis–driven basal cell hyperplasia
Margarette H. Clevenger, Adam L. Karami, Dustin A. Carlson, Peter J. Kahrilas, Nirmala Gonsalves, John E. Pandolfino, Deborah R. Winter, Kelly A. Whelan, Marie-Pier Tétreault
Margarette H. Clevenger, Adam L. Karami, Dustin A. Carlson, Peter J. Kahrilas, Nirmala Gonsalves, John E. Pandolfino, Deborah R. Winter, Kelly A. Whelan, Marie-Pier Tétreault
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Research Article Gastroenterology Inflammation

Suprabasal cells retain progenitor cell identity programs in eosinophilic esophagitis–driven basal cell hyperplasia

Abstract

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH). Although BCH is known to correlate with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that BCH is predominantly characterized by an expansion of nonproliferative suprabasal cells that are still committed to early differentiation. Furthermore, we discovered that suprabasal and superficial esophageal epithelial cells retain progenitor identity programs in EoE, evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these alterations were not observed in gastroesophageal reflux disease. These findings provide additional insights into the differentiation process in EoE and highlight the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease.

Authors

Margarette H. Clevenger, Adam L. Karami, Dustin A. Carlson, Peter J. Kahrilas, Nirmala Gonsalves, John E. Pandolfino, Deborah R. Winter, Kelly A. Whelan, Marie-Pier Tétreault

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Figure 10

The distinct molecular changes identified at a single-cell level in EEC in EoE are not detected in GERD.

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The distinct molecular changes identified at a single-cell level in EEC ...
(A) Scatterplots of DEGs calculated per epithelial compartment between HC and EoE (|logFC| > 0.5, FDR-adjusted P < 0.05). Each gene is plotted as logFC in EoE compared with HC (y axis) versus logFC in GERD compared with HC (x axis). Color indicates the direction and magnitude of logFC in EoE and GERD. Red (logFC > 0.5 only in EoE), blue (logFC < -0.5 only in EoE), green (logFC > 0.5 in EoE and GERD, or logFC < -0.5 in EoE and GERD), and purple (logFC > 0.5 in EoE and < –0.5 in GERD, or logFC < –0.5 in EoE and > 0.5 in GERD). For each compartment, a pie chart summarizes the direction and magnitude of logFCs in EoE and GERD. (B) Comparison of average expression Z scores of known epithelial transcription factors and differentiation markers in EEC compartments across HC, EoE, and GERD. Color gradient indicates the average gene expression level for each cluster. The dot size corresponds to the percentage of cells within each cluster exhibiting gene expression. (C) Violin plots displaying the gene signature scores derived from DEGs specific to suprabasal and superficial compartments in EoE that were hierarchically clustered as shown in Supplemental Figure 10A. Enriched terms associated with each hierarchical cluster are indicated. These scores are shown for each EEC compartment in HC, EoE, and GERD. (D and E) Violin plots showing quiescent and superficial gene signature scores (D) or SOX2 and KLF5 expression (E) for each EEC compartment in HC, EoE, or GERD. B, Basal; SB, Suprabasal; SF, Superficial; Padj, FDR-adjusted P value.