TY - JOUR
T1 - Barrett’s metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux
AU - Minacapelli, Carlos D.
AU - Bajpai, Manisha
AU - Geng, Xin
AU - Cheng, Christina L.
AU - Chouthai, Abhishek A.
AU - Souza, Rhonda
AU - Spechler, Stuart J.
AU - Das, Kiron M.
N1 - Funding Information:
We thank Dr. Borivoj Vojtesek from the Masaryk Memorial Cancer Institute (Brno, Czech Republic) for providing the TAp63 antibody. We also thank Theresa Hyejeong Choi, Jessica Cervelli, and Arthur Roberts for support with flow cytometry at Rutgers Core Facility. Part of this work was presented at the annual meeting of the American Gastroenterological Association held in May 2015 in Washington, DC. This work was supported in part by Gastrointestinal Divisional funds (The Rutgers Robert Wood Johnson Medical School, Department of Medicine, Division of Gastroenterology), a fellowship grant from Takeda Pharmaceuticals and also in part by Aresty Research Center grants.
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/6
Y1 - 2017/6
N2 - Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett’s metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/ day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells. NEW & NOTEWORTHY This study provides evidence of the origins of Barrett’s metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett’s metaplasia and esophageal adenocarcinoma.
AB - Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett’s metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/ day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells. NEW & NOTEWORTHY This study provides evidence of the origins of Barrett’s metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett’s metaplasia and esophageal adenocarcinoma.
KW - Barrett’s metaplasia
KW - Biphenotypic
KW - GERD
KW - Reprogramming
KW - Transcommitment
UR - http://www.scopus.com/inward/record.url?scp=85020208519&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020208519&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00268.2016
DO - 10.1152/ajpgi.00268.2016
M3 - Article
C2 - 28336546
AN - SCOPUS:85020208519
SN - 0193-1857
VL - 312
SP - G615-G622
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 6
ER -