Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group

doi:10.1053/j.gastro.2021.10.016

Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Background & Aims: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. Methods: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. Results: TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. Conclusions: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

Original language	English (US)
Pages (from-to)	439-453
Number of pages	15
Journal	Gastroenterology
Volume	162
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2021.10.016
State	Published - Feb 2022

Funding

Funding This study was supported by CEGIR (U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is co-funded by the National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, and NCATS. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Disease, and Eosinophilic Family Coalition. As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (U2CTR002818).

Keywords

Endothelium
Eosinophil
Eosinophilic Esophagitis
Fibrosis
Transcriptome

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2021.10.016

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@article{92aa03fe97ca4955968426ffc174d247,

title = "Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk",

abstract = "Background & Aims: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. Methods: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. Results: TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. Conclusions: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.",

keywords = "Endothelium, Eosinophil, Eosinophilic Esophagitis, Fibrosis, Transcriptome",

author = "{Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group} and Tetsuo Shoda and Ting Wen and Caldwell, {Julie M.} and {Ben-Baruch Morgenstern}, Netali and Osswald, {Garrett A.} and Mark Rochman and Mack, {Lydia E.} and Felton, {Jennifer M.} and Abonia, {J. Pablo} and Arva, {Nicoleta C.} and Dan Atkins and Bonis, {Peter A.} and Capocelli, {Kelley E.} and Collins, {Margaret H.} and Dellon, {Evan S.} and Falk, {Gary W.} and Nirmala Gonsalves and Gupta, {Sandeep K.} and Ikuo Hirano and John Leung and Menard-Katcher, {Paul A.} and Mukkada, {Vincent A.} and Putnam, {Philip E.} and {Rudman Spergel}, {Amanda K.} and Spergel, {Jonathan M.} and Wechsler, {Joshua B.} and Yang, {Guang Yu} and Aceves, {Seema S.} and Furuta, {Glenn T.} and Rothenberg, {Marc E.} and Seema Aceves and Samuel Almonte and Rachel Andrews and Ashley Arrington and Nicoleta Arva and Fred Atkins and Dominique Bailey and Alexis Berry and Bridget Besl and Scott Bolton and Peter Bonis and Wendy Book and Kimberly Bray and Teresa Brown and Cassandra Burger and Deirdre Burke and Jonathon Cahoon and Amir Kagalwalla and Joshua Wechsler and Barry Wershil",

note = "Publisher Copyright: {\textcopyright} 2022 AGA Institute",

year = "2022",

month = feb,

doi = "10.1053/j.gastro.2021.10.016",

language = "English (US)",

volume = "162",

pages = "439--453",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "2",

}

TY - JOUR

T1 - Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

AU - Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators Group

AU - Shoda, Tetsuo

AU - Wen, Ting

AU - Caldwell, Julie M.

AU - Ben-Baruch Morgenstern, Netali

AU - Osswald, Garrett A.

AU - Rochman, Mark

AU - Mack, Lydia E.

AU - Felton, Jennifer M.

AU - Abonia, J. Pablo

AU - Arva, Nicoleta C.

AU - Atkins, Dan

AU - Bonis, Peter A.

AU - Capocelli, Kelley E.

AU - Collins, Margaret H.

AU - Dellon, Evan S.

AU - Falk, Gary W.

AU - Gonsalves, Nirmala

AU - Gupta, Sandeep K.

AU - Hirano, Ikuo

AU - Leung, John

AU - Menard-Katcher, Paul A.

AU - Mukkada, Vincent A.

AU - Putnam, Philip E.

AU - Rudman Spergel, Amanda K.

AU - Spergel, Jonathan M.

AU - Wechsler, Joshua B.

AU - Yang, Guang Yu

AU - Aceves, Seema S.

AU - Furuta, Glenn T.

AU - Rothenberg, Marc E.

AU - Aceves, Seema

AU - Almonte, Samuel

AU - Andrews, Rachel

AU - Arrington, Ashley

AU - Arva, Nicoleta

AU - Atkins, Fred

AU - Bailey, Dominique

AU - Berry, Alexis

AU - Besl, Bridget

AU - Bolton, Scott

AU - Bonis, Peter

AU - Book, Wendy

AU - Bray, Kimberly

AU - Brown, Teresa

AU - Burger, Cassandra

AU - Burke, Deirdre

AU - Cahoon, Jonathon

AU - Kagalwalla, Amir

AU - Wechsler, Joshua

AU - Wershil, Barry

PY - 2022/2

Y1 - 2022/2

N2 - Background & Aims: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. Methods: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. Results: TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. Conclusions: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

AB - Background & Aims: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. Methods: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. Results: TSPAN12 was the gene most correlated with fibrostenosis (r = −0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34–0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = −0.41, P < .001), and genes enriched in cell cycle–related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti–IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell–fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. Conclusions: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

KW - Endothelium

KW - Eosinophil

KW - Eosinophilic Esophagitis

KW - Fibrosis

KW - Transcriptome

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U2 - 10.1053/j.gastro.2021.10.016

DO - 10.1053/j.gastro.2021.10.016

M3 - Article

C2 - 34687736

AN - SCOPUS:85121747513

SN - 0016-5085

VL - 162

SP - 439

EP - 453

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

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