Single-cell RNA-Seq of human esophageal epithelium in homeostasis and allergic inflammation

Rochman, Mark; Wen, Ting; Kotliar, Michael; Dexheimer, Phillip; Morgenstern, Netali Ben-Baruch; Caldwell, Julie M.; Lim, Hee‐Woong; Rothenberg, Marc E.

doi:10.1172/jci.insight.159093

Cited by 50 publications

(57 citation statements)

References 60 publications

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“…As such, it will be of interest to determine how EoE inflammation impacts the expression of ATP1B3. A recent human scRNA-Seq study identified an increase in proliferating suprabasal cells, but not proliferating basal cells, in the epithelium of active EoE subjects (45). Identification of proliferating cells in the noted human EoE dataset was based on expression of the proliferation marker TOP2A (45).…”

Section: Discussionmentioning

confidence: 99%

“…A recent human scRNA-Seq study identified an increase in proliferating suprabasal cells, but not proliferating basal cells, in the epithelium of active EoE subjects (45). Identification of proliferating cells in the noted human EoE dataset was based on expression of the proliferation marker TOP2A (45). Although we did not evaluate Top2a , analysis of cell cycle genes in our dataset does not support proliferation across the EoE-enriched suprabasal populations and pathway analysis in these clusters predicted an association with senescence pathway.…”

Section: Discussionmentioning

confidence: 99%

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Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

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Karami

Kabir

et al. 2022

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Under homeostatic conditions, esophageal epithelium displays a proliferation/differentiation gradient that is generated as proliferative basal cells give rise to suprabasal cells then terminally differentiated superficial cells. This proliferation/differentiation gradient is perturbed in esophageal pathologies both benign and malignant. Esophageal cancer is among the deadliest forms of human malignancy with 5-year survival rates of <20%. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common subtypes of esophageal cancer. Gastroesophageal reflux disease (GERD) is a primary risk factor for EAC. Although GERD and the food allergy-mediated condition eosinophilic esophagitis (EoE) are both associated with chronic esophageal inflammation and epithelial remodeling, including basal cell hyperplasia, epidemiological evidence suggests that EoE patients do not develop esophageal malignancy. Here, we perform single cell RNA-sequencing in murine models of EoE and ESCC to delineate the effects that these two conditions have specifically upon the cellular landscape of esophageal epithelium. In mice with EoE or ESCC, we find expansion of cell populations as compared to normal esophageal epithelium. In mice with EoE, we detect expansion of 4 suprabasal populations coupled with depletion of 4 basal cell populations. By contrast, mice with ESCC display expansion of 4 basal populations as well as depletion of 3 superficial populations. We further evaluated modules of co-expressed genes in EoE- and ESCC-enriched epithelial cell clusters. Senescence, glucocorticoid receptor signaling, and granulocyte-macrophage colony-stimulating factor pathways were associated with EoE-enriched clusters while pathways associated with cell proliferation and metabolism were identified in ESCC-enriched clusters. Finally, by pairing murine models of EoE and ESCC, we demonstrate that exposure to EoE inflammation limits esophageal carcinogenesis. Our findings provide the first functional investigation of the relationship between EoE and esophageal cancer and suggest that esophageal epithelial remodeling events occurring in response to EoE inflammation may limit act to esophageal carcinogenesis which may have future implications for leveraging allergic inflammation-associated alterations in epithelial biology to prevent and/or treat esophageal cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

Fuller

Karami

Kabir

et al. 2022

Preprint

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“…Consistent with EoE-associated alterations in cell cycle within esophageal keratinocytes, a recent human scRNA-Seq study identified an increase in proliferating suprabasal cells, but not proliferating basal cells, in the epithelium of active EoE subjects ( 42 ). Identification of proliferating cells in the noted human EoE dataset was based on expression of the proliferation marker TOP2A ( 42 ). Interestingly, Top2a expression is highly upregulated in the EoE-enriched murine population suprabasal 5 in our dataset ( Figure 1D ) which further displays enrichment of genes associated with G2/M phase of the cell cycle ( Figure 4C ).…”

Section: Discussionmentioning

confidence: 75%

“…Thus, it is further possible that cells located in the basal cell layer of mice with EoE take on features of the suprabasal cell compartment (Figure 8), including exit from the cell cycle. Consistent with EoE-associated alterations in cell cycle within esophageal keratinocytes, a recent human scRNA-Seq study identified an increase in proliferating suprabasal cells, but not proliferating basal cells, in the epithelium of active EoE subjects (42). Identification of proliferating cells in the noted human EoE dataset was based on expression of the proliferation marker TOP2A (42).…”

Section: Discussionmentioning

confidence: 87%

Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

et al. 2023

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IntroductionUnder homeostatic conditions, esophageal epithelium displays a proliferation/differentiation gradient that is generated as proliferative basal cells give rise to suprabasal cells then terminally differentiated superficial cells. This proliferation/differentiation gradient is often perturbed in esophageal pathologies. Basal cell hyperplasia may occur in patients with gastroesophageal reflux disease (GERD), a condition in which acid from the stomach enters the esophagus, or eosinophilic esophagitis (EoE), an emerging form of food allergy. While GERD is a primary risk factor for esophageal cancer, epidemiological data suggests that EoE patients do not develop esophageal cancer.MethodsIn order to investigate the impact of EoE and esophageal cancer specifically on the cellular landscape of esophageal epithelium, we perform single cell RNA-sequencing in murine models of EoE and esophageal cancer, specifically esophageal squamous cell carcinoma (ESCC). We further evaluate modules of co-expressed genes in EoE- and ESCC-enriched epithelial cell clusters. Finally, we pair EoE and ESCC murine models to examine the functional relationship between these pathologies.ResultsIn mice with either EoE or ESCC, we find expansion of cell populations as compared to normal esophageal epithelium. In mice with EoE, we detect distinct expansion of 4 suprabasal populations coupled with depletion of 2 basal populations. By contrast, mice with ESCC display unique expansion of 2 basal populations and 1 suprabasal population, as well as depletion of 2 suprabasal populations. Senescence, glucocorticoid receptor signaling, and granulocyte-macrophage colony-stimulating factor pathways are associated with EoE-enriched clusters while pathways associated with cell proliferation and metabolism are identified in ESCC-enriched clusters. Finally, our in vivo data demonstrate that exposure to EoE inflammation limits tumor burden of esophageal carcinogenesis.DiscussionOur findings provide the first functional investigation of the relationship between EoE and esophageal cancer and suggest that esophageal epithelial remodeling events occurring in response to EoE inflammation may limit esophageal carcinogenesis. This investigation may have future implications for leveraging allergic inflammation-associated alterations in epithelial biology to prevent and/or treat esophageal cancer.

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“…Since its inception in 2019, it has demonstrated its utility at the local laboratory level and beyond such as by generating interest from collaborators in academia and industry. At least 12 publications have already been facilitated by EGIDExpress 15, 16, 17, 18, 19,20, 21, 14, 22, 23, 24, 25 . Datasets will continue to be added to EGIDExpress as they are generated, and we remain flexible to adding new data formats or modes of visualization as new dataset types arise, and we are open to developing new functionalities within the app.…”

Section: Resultsmentioning

confidence: 99%

EGIDExpress: An Interactive Shiny Web App to Visualize and Share Large Biological Datasets

Besse

Osswald

Ballaban

et al. 2022

Preprint

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Biomedical research on rare diseases faces challenges such as low availability of biological specimens to study and limited funding. Eosinophilic gastrointestinal diseases (EGIDs) are rare conditions associated with inappropriate inflammation and the accumulation of eosinophils in various segments of the gastrointestinal tract. We aimed to build a repository of large datasets related to EGIDs that would be easily browsable, interpretable, and accessible in order to facilitate data sharing and hypothesis generation. Using the R-code based package Shiny, we built a website that allows visualization of multiple types of datasets including microarray, RNAseq, protein array, single-cell RNAseq, and ChIPseq. Users can access EGIDExpress (https://egidexpress.research.cchmc.org/) to browse data on a per-gene basis and to generate graphic representation of the data. Additionally, users can download the processed data to initiate their own analyses. Within 34 months of launching EGIDExpress, over 2400 users from 37 countries and 37 states within the United States accessed the site. Overall, EGIDExpress is accelerating research on EGIDs and provides a prototypic platform for broad research data sharing.

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Single-cell RNA-Seq of human esophageal epithelium in homeostasis and allergic inflammation

Cited by 50 publications

References 60 publications

Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

EGIDExpress: An Interactive Shiny Web App to Visualize and Share Large Biological Datasets

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