Suprabasal cells retaining stem cell identity programs drive basal cell hyperplasia in eosinophilic esophagitis

Author:

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

Abstract

AbstractEosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH) and loss of differentiation. Although BCH correlates with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that despite the presence of BCH in all EoE patients examined, no increase in basal cell proportion was observed by scRNA-seq. Instead, EoE patients exhibited a reduced pool ofKRT15+ COL17A1+quiescent cells, a modest increase inKI67+dividing epibasal cells, a substantial increase inKRT13+ IVL+suprabasal cells, and a loss of differentiated identity in superficial cells. Suprabasal and superficial cell populations demonstrated increased quiescent cell identity scoring in EoE with the enrichment of signaling pathways regulating pluripotency of stem cells. However, this was not paired with increased proliferation. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these findings were not observed in GERD. Thus, our study demonstrates that BCH in EoE results from an expansion of non-proliferative cells that retain stem-like transcriptional programs while remaining committed to early differentiation.

Publisher

Cold Spring Harbor Laboratory

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