Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

Erwin Brosens; Janine F. Felix; Anne Boerema-de Munck; Elisabeth M. de Jong; Elisabeth M. Lodder; Sigrid Swagemakers; Marjon Buscop-van Kempen; Ronald R. de Krijger; Rene M.H. Wijnen; Wilfred F.J. van IJcken; Peter van der Spek; Annelies de Klein; Dick Tibboel; Robbert J. Rottier

doi:10.1371/journal.pone.0242167

Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

Erwin Brosens, Janine F. Felix, Anne Boerema-de Munck, Elisabeth M. de Jong, Elisabeth M. Lodder, Sigrid Swagemakers, Marjon Buscop-van Kempen, Ronald R. de Krijger, Rene M.H. Wijnen, Wilfred F.J. van IJcken, Peter van der Spek, Annelies de Klein, Dick Tibboel, Robbert J. Rottier

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Abstract

Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that its etiology should not be sought in cell fate specification.

Original language	English
Article number	e0242167
Pages (from-to)	1-24
Journal	PLoS ONE
Volume	15
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0242167
Publication status	Published - Nov 2020

Keywords

Actin Cytoskeleton/genetics
Adult
Bone Morphogenetic Proteins/genetics
Esophagus/metabolism
Extracellular Matrix/genetics
Female
Fibrosis
Humans
Lung/metabolism
Male
Signal Transduction
Trachea/metabolism
Tracheoesophageal Fistula/genetics
Transcriptome

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Brosens, E., Felix, J. F., Boerema-de Munck, A., de Jong, E. M., Lodder, E. M., Swagemakers, S., Buscop-van Kempen, M., de Krijger, R. R., Wijnen, R. M. H., van IJcken, W. F. J., van der Spek, P., de Klein, A., Tibboel, D., & Rottier, R. J. (2020). Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas. PLoS ONE, 15(11), 1-24. Article e0242167. https://doi.org/10.1371/journal.pone.0242167

@article{0d62fd9a11694b39b22d0621b8fa7be4,

title = "Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas",

abstract = "Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that its etiology should not be sought in cell fate specification.",

keywords = "Actin Cytoskeleton/genetics, Adult, Bone Morphogenetic Proteins/genetics, Esophagus/metabolism, Extracellular Matrix/genetics, Female, Fibrosis, Humans, Lung/metabolism, Male, Signal Transduction, Trachea/metabolism, Tracheoesophageal Fistula/genetics, Transcriptome",

author = "Erwin Brosens and Felix, {Janine F.} and {Boerema-de Munck}, Anne and {de Jong}, {Elisabeth M.} and Lodder, {Elisabeth M.} and Sigrid Swagemakers and {Buscop-van Kempen}, Marjon and {de Krijger}, {Ronald R.} and Wijnen, {Rene M.H.} and {van IJcken}, {Wilfred F.J.} and {van der Spek}, Peter and {de Klein}, Annelies and Dick Tibboel and Rottier, {Robbert J.}",

note = "Funding Information: This work was supported by the Edgar Doncker Foundation [DT; J.F.F.] and the Sophia Foundation for Scientific Research [Grant Numbers 493 [DT; ADK; E.M.de J.], 436 [A.de M.] and S13-09 [DT; ADK; E.B.] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright {\textcopyright} 2020 Brosens et al. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = nov,

doi = "10.1371/journal.pone.0242167",

language = "English",

volume = "15",

pages = "1--24",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "11",

}

Brosens, E, Felix, JF, Boerema-de Munck, A, de Jong, EM, Lodder, EM, Swagemakers, S, Buscop-van Kempen, M, de Krijger, RR, Wijnen, RMH, van IJcken, WFJ, van der Spek, P, de Klein, A, Tibboel, D & Rottier, RJ 2020, 'Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas', PLoS ONE, vol. 15, no. 11, e0242167, pp. 1-24. https://doi.org/10.1371/journal.pone.0242167

TY - JOUR

T1 - Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

AU - Brosens, Erwin

AU - Felix, Janine F.

AU - Boerema-de Munck, Anne

AU - de Jong, Elisabeth M.

AU - Lodder, Elisabeth M.

AU - Swagemakers, Sigrid

AU - Buscop-van Kempen, Marjon

AU - de Krijger, Ronald R.

AU - Wijnen, Rene M.H.

AU - van IJcken, Wilfred F.J.

AU - van der Spek, Peter

AU - de Klein, Annelies

AU - Tibboel, Dick

AU - Rottier, Robbert J.

N1 - Funding Information: This work was supported by the Edgar Doncker Foundation [DT; J.F.F.] and the Sophia Foundation for Scientific Research [Grant Numbers 493 [DT; ADK; E.M.de J.], 436 [A.de M.] and S13-09 [DT; ADK; E.B.] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright © 2020 Brosens et al. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/11

Y1 - 2020/11

N2 - Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that its etiology should not be sought in cell fate specification.

AB - Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are relatively frequently occurring foregut malformations. EA/TEF is thought to have a strong genetic component. Not much is known regarding the biological processes disturbed or which cell type is affected in patients. This hampers the detection of the responsible culprits (genetic or environmental) for the origin of these congenital anatomical malformations. Therefore, we examined gene expression patterns in the TEF and compared them to the patterns in esophageal, tracheal and lung control samples. We studied tissue organization and key proteins using immunohistochemistry. There were clear differences between TEF and control samples. Based on the number of differentially expressed genes as well as histological characteristics, TEFs were most similar to normal esophagus. The BMP-signaling pathway, actin cytoskeleton and extracellular matrix pathways are downregulated in TEF. Genes involved in smooth muscle contraction are overexpressed in TEF compared to esophagus as well as trachea. These enriched pathways indicate myofibroblast activated fibrosis. TEF represents a specific tissue type with large contributions of intestinal smooth muscle cells and neurons. All major cell types present in esophagus are present-albeit often structurally disorganized-in TEF, indicating that its etiology should not be sought in cell fate specification.

KW - Actin Cytoskeleton/genetics

KW - Adult

KW - Bone Morphogenetic Proteins/genetics

KW - Esophagus/metabolism

KW - Extracellular Matrix/genetics

KW - Female

KW - Fibrosis

KW - Humans

KW - Lung/metabolism

KW - Male

KW - Signal Transduction

KW - Trachea/metabolism

KW - Tracheoesophageal Fistula/genetics

KW - Transcriptome

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U2 - 10.1371/journal.pone.0242167

DO - 10.1371/journal.pone.0242167

M3 - Article

C2 - 33201890

AN - SCOPUS:85096348581

SN - 1932-6203

VL - 15

SP - 1

EP - 24

JO - PLoS ONE

JF - PLoS ONE

IS - 11

M1 - e0242167

ER -

Histological, immunohistochemical and transcriptomic characterization of human tracheoesophageal fistulas

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