A unique esophageal extracellular matrix proteome alters normal fibroblast function in severe eosinophilic esophagitis - 04/08/21
Abstract |
Background |
Eosinophilic esophagitis (EoE) is a chronic TH2 disorder complicated by tissue fibrosis and loss of esophageal luminal patency. The fibrostenotic esophagus does not respond well to therapy, but profibrotic therapeutic targets are largely unclear.
Objective |
Our aim was to utilize proteomics and primary cells as a novel approach to determine relevant profibrotic factors.
Methods |
We utilized primary esophageal EoE and normal fibroblasts, their derivative extracellular matrixes (ECMs), an approach of fibroblast culture on autologous versus nonautologous ECM, and proteomics to elucidate EoE ECM proteins that dysregulate cellular function.
Results |
We cultured esophageal fibroblasts from normal esophagi and esophagi from patients with severe EoE on autologous versus nonautologous ECM. The EoE ECM proteome shifted normal esophageal fibroblast protein expression. Proteomic analysis demonstrated that thrombospondin-1 is detected only in the EoE ECM, is central in the EoE ECM protein-protein interactome, is found at significantly elevated levels in biopsy specimens from patients with active EoE, and induces fibroblast collagen I production.
Conclusion |
Fibroblasts from patients with EoE secrete a unique ECM proteome that reflects their in vivo state and induces collagen I and α-smooth muscle actin protein expression from normal fibroblasts. Thrombospondin-1 is a previously unappreciated profibrotic molecule in EoE.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Eosinophil, esophagus, fibrosis, interactome, remodeling, thrombospondin-1
Abbreviations used : DAVID, DEP, ECM, EndoFLIP, EoE, ES, GO, GSEA, hpf, LFQ, PPI, α-SMA, STRING, TSP-1, UPLC, UPLC-MS/MS
Plan
| Supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases/National Institute of Diabetes and Digestive and Kidney Diseases (grants R01AI092135 [to S.S.A.], K24AI135034 [to S.S.A.], R21AI154353 [to S.S.A.], and R01DK114457 [to S.S.A.]). In addition, the Novo Nordisk Foundation provided funding to the Center for Biosustainability at the Technical University of Denmark (grants NNF10CC1016517 [to A.W.T.C.] and R35 GM119850 [to N.E.L.]). |
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| Disclosure of potential conflict of interest: S. S. Aceves and R. Dohil are coinventors of oral viscous budesonide patented by the University of California, San Diego, and licensed by Takeda. S. S. Aceves has consulting agreements with AstraZeneca, Astellas, AImmune, Medscape, UptoDate, and Gossamer Bio. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 148 - N° 2
P. 486-494 - août 2021 Retour au numéro
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