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Molecular Mechanisms of Epithelial Contribution to the Pathogenesis of Eosinophilic Esophagitis: From Single Cell Transcriptomics to the Generation of a New Experimental Mouse Model /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Molecular Mechanisms of Epithelial Contribution to the Pathogenesis of Eosinophilic Esophagitis: From Single Cell Transcriptomics to the Generation of a New Experimental Mouse Model // Margarette Clevenger.
Author:	Clevenger, Margarette,
Description:	1 electronic resource (179 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
Contained By:	Dissertations Abstracts International86-02B.
Subject:	Biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31488397
ISBN:	9798384015864

Molecular Mechanisms of Epithelial Contribution to the Pathogenesis of Eosinophilic Esophagitis: From Single Cell Transcriptomics to the Generation of a New Experimental Mouse Model /
Clevenger, Margarette,

Molecular Mechanisms of Epithelial Contribution to the Pathogenesis of Eosinophilic Esophagitis: From Single Cell Transcriptomics to the Generation of a New Experimental Mouse Model /Margarette Clevenger. - 1 electronic resource (179 pages)

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

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 demonstrated that BCH is predominantly characterized by an expansion of non-proliferative 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, which was evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SRY (sex-determining region Y)-box 2 (SOX2) and Kruppel-like factor 5 (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 (GERD). Future studies characterizing esophageal epithelial transcriptomic changes in EoE patients treated with Dupilimab will determine whether SOX2 and KLF5 overexpression and downstream epithelial remodeling are IL-13 dependent. These findings offer further insights into the differentiation process in EoE, underscore the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease, and emphasize the epithelium as a potential target for future EoE treatments.The use of mouse models allows for the faithful replication of various temporal aspects of EoE pathology, including allergic sensitization, esophageal antigen exposure, and the development of the innate and adaptive immune response. Further, mouse models enable the investigation of key molecular and cellular mechanisms underlying EoE development and progression and provides a platform for testing putative therapeutic interventions. Current mouse models, while having provided meaningful contributions to the field, often fail to capture the entirety of human disease features, particularly concerning epithelial alterations. Without a model that faithfully replicates these aspects, elucidating the molecular drivers behind basal cell hyperplasia and assessing treatments targeted to the esophageal epithelium remain challenging.The esophageal epithelium is a central driver of EoE disease and esophageal epithelial-specific genes harbor many of the genetic risk factors for EoE development. It is possible that altered epithelial signaling is required for the development of a robust and accurate mouse model of EoE. We observed alterations in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in human EoE mucosal biopsies, a pathway that acts as a central signaling nexus in inflammatory responses and governs essential biological processes crucial for maintaining homeostasis, encompassing inflammation, immunity, and cell survival. Dysregulation of this pathway has been linked to various inflammatory diseases and cancers. To address a possible role of canonical NF-κB in EoE pathogenesis, conditional knockout of inhibitor of nuclear factor kappa-B kinase subunit beta (Ikkβ) knockout was induced in esophageal epithelial cells in mice sensitized with MC903/Ovalbumin (OVA), followed by intraesophageal OVA challenge (IkkβEEC-KO/EoE). Notably, this model faithfully recapitulated key histological and transcriptional features observed in human EoE patients, encompassing inflammatory components, fibrosis, and a comprehensive representation of epithelial alterations, including the presence of intraepithelial eosinophils, eosinophil microabscesses, intracellular space dilatation, basal cell hyperplasia, and the presence of dyskeratotic epithelial cells. These findings suggest a role of altered IKKβ/NF-κB signaling in EoE pathogenesis. Finally, extensive histological and transcriptomic comparison of the IkkβEEC-KO/EoE mouse model to human EoE establishes the model as a promising platform for the study of epithelial alterations and epithelial-targeted treatments in EoE.

English

ISBN: 9798384015864Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Basal cell hyperplasia

Molecular Mechanisms of Epithelial Contribution to the Pathogenesis of Eosinophilic Esophagitis: From Single Cell Transcriptomics to the Generation of a New Experimental Mouse Model /
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520 $a 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 demonstrated that BCH is predominantly characterized by an expansion of non-proliferative 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, which was evidenced by increased quiescent cell identity scoring and the enrichment of signaling pathways regulating stem cell pluripotency. Enrichment and trajectory analyses identified SRY (sex-determining region Y)-box 2 (SOX2) and Kruppel-like factor 5 (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 (GERD). Future studies characterizing esophageal epithelial transcriptomic changes in EoE patients treated with Dupilimab will determine whether SOX2 and KLF5 overexpression and downstream epithelial remodeling are IL-13 dependent. These findings offer further insights into the differentiation process in EoE, underscore the distinct characteristics of suprabasal and superficial esophageal epithelial cells in the disease, and emphasize the epithelium as a potential target for future EoE treatments.The use of mouse models allows for the faithful replication of various temporal aspects of EoE pathology, including allergic sensitization, esophageal antigen exposure, and the development of the innate and adaptive immune response. Further, mouse models enable the investigation of key molecular and cellular mechanisms underlying EoE development and progression and provides a platform for testing putative therapeutic interventions. Current mouse models, while having provided meaningful contributions to the field, often fail to capture the entirety of human disease features, particularly concerning epithelial alterations. Without a model that faithfully replicates these aspects, elucidating the molecular drivers behind basal cell hyperplasia and assessing treatments targeted to the esophageal epithelium remain challenging.The esophageal epithelium is a central driver of EoE disease and esophageal epithelial-specific genes harbor many of the genetic risk factors for EoE development. It is possible that altered epithelial signaling is required for the development of a robust and accurate mouse model of EoE. We observed alterations in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in human EoE mucosal biopsies, a pathway that acts as a central signaling nexus in inflammatory responses and governs essential biological processes crucial for maintaining homeostasis, encompassing inflammation, immunity, and cell survival. Dysregulation of this pathway has been linked to various inflammatory diseases and cancers. To address a possible role of canonical NF-κB in EoE pathogenesis, conditional knockout of inhibitor of nuclear factor kappa-B kinase subunit beta (Ikkβ) knockout was induced in esophageal epithelial cells in mice sensitized with MC903/Ovalbumin (OVA), followed by intraesophageal OVA challenge (IkkβEEC-KO/EoE). Notably, this model faithfully recapitulated key histological and transcriptional features observed in human EoE patients, encompassing inflammatory components, fibrosis, and a comprehensive representation of epithelial alterations, including the presence of intraepithelial eosinophils, eosinophil microabscesses, intracellular space dilatation, basal cell hyperplasia, and the presence of dyskeratotic epithelial cells. These findings suggest a role of altered IKKβ/NF-κB signaling in EoE pathogenesis. Finally, extensive histological and transcriptomic comparison of the IkkβEEC-KO/EoE mouse model to human EoE establishes the model as a promising platform for the study of epithelial alterations and epithelial-targeted treatments in EoE.
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