1. Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk
- Author
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Tetsuo Shoda, Ting Wen, Julie M. Caldwell, Netali Ben-Baruch Morgenstern, Garrett A. Osswald, Mark Rochman, Lydia E. Mack, Jennifer M. Felton, J. Pablo Abonia, Nicoleta C. Arva, Dan Atkins, Peter A. Bonis, Kelley E. Capocelli, Margaret H. Collins, Evan S. Dellon, Gary W. Falk, Nirmala Gonsalves, Sandeep K. Gupta, Ikuo Hirano, John Leung, Paul A. Menard-Katcher, Vincent A. Mukkada, Philip E. Putnam, Amanda K. Rudman Spergel, Jonathan M. Spergel, Joshua B. Wechsler, Guang-Yu Yang, Seema S. Aceves, Glenn T. Furuta, Marc E. Rothenberg, Seema Aceves, Samuel Almonte, Rachel Andrews, Ashley Arrington, Nicoleta Arva, Fred Atkins, Dominique Bailey, Alexis Berry, Bridget Besl, Scott Bolton, Peter Bonis, Wendy Book, Kimberly Bray, Teresa Brown, Cassandra Burger, Deirdre Burke, Jonathon Cahoon, Kelley Capocelli, Mirna Chehade, Margaret Collins, Carla Davis, Evan Dellon, Maureen DeMarshall, Lauren DiTommaso, Ranjan Dohil, Michael Eby, Gary Falk, David Fleischer, Heather Foote, Kelci Foss, Joel Friedlander, Patricia Fulkerson, Glenn Furuta, Debra Geno, Thomas Greuter, Sandeep Gupta, Frank Hamilton, Kirk Harris, Jennifer Harris, Girish Hiremath, Nicole Holland-Thomas, Lea Jacinto, Amir Kagalwalla, Timothy Kaseta, David Katzka, Kaitlin Keeley, Emad Khosh-Hemmat, Paneez Khoury, Eileen King, Kara Kliewer, Amy Klion, Jennifer Knowles, Kendra Kocher, Ellyn Kodroff, Jeffrey Krischer, Shay Kyle, Meredith Levy, Chris Liacouras, Denise Mack, Lisa Martin, Ellen Martin, Talaya McCright-Gill, Paul Menard-Katcher, Calies Menard-Katcher, Gabriela Mendoza, Melissa Mingler, Mike Minnicozzi, Amanda Muir, Vincent Mukkada, Cristin MurrayPetzold, Robert Newbury, Quan Nhu, Oghenekpaobor (Joel) Oyibo, Allisa Paliana, Zhaoxing Pan, Robbie Pesek, Kathryn Peterson, Heidi Poppendeck, Philip Putnam, Fabian Rivera, Marc Rothenberg, Amanda Rudman Spergel, Kathleen Sable, Alain Schoepfer, Melissa Scott, Rachel Sheridan, Selma Sinanovic, Jonathan Spergel, MaryJo Strobel, Kiki Sun, Amy Tasco, Crystal Tholen, Katherine Thompson, Tiffany Tomkinson, Daisy Tran, Alexandra Tylicki, Tiina Urv, Mei-Lun Wang, Joshua Wechsler, Barry Wershil, Lisa Wheatley, Leah Wilkey, Angelika Zalewski, and Amy Zicarelli
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Thymic stromal lymphopoietin ,Adolescent ,Endothelium ,Tetraspanins ,medicine.drug_class ,Proton-pump inhibitor ,Young Adult ,Esophagus ,Fibrosis ,Eosinophilic ,medicine ,Humans ,Gene Silencing ,RNA, Small Interfering ,Child ,Eosinophilic esophagitis ,Interleukin-13 ,Hepatology ,business.industry ,Gastroenterology ,Endothelial Cells ,Eosinophilic Esophagitis ,Fibroblasts ,Middle Aged ,Eosinophil ,medicine.disease ,medicine.anatomical_structure ,Gene Expression Regulation ,Gastrointestinal disease ,Child, Preschool ,Esophageal Stenosis ,Female ,business - Abstract
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.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.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.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.
- Published
- 2022
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