Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux.
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 & NOTEWORTHYThis 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.
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
Carlos D
CD
Minacapelli
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and bajpaima@rwjms.rutgers.edu bajpaima@gmail.com.
Manisha
M
Bajpai
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
Xin
X
Geng
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
Christina L
CL
Cheng
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
Abhishek A
AA
Chouthai
Veterans Affairs North Texas Health Care System-Dallas and the University of Texas Southwestern Medical Center, Dallas, Texas.
Rhonda
R
Souza
Veterans Affairs North Texas Health Care System-Dallas and the University of Texas Southwestern Medical Center, Dallas, Texas.
Stuart J
SJ
Spechler
Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; and.
Kiron M
KM
Das
D001471:Barrett Esophagus / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D019070:Cell Lineage; D048430:Cell Shape; D065150:Cellular Reprogramming / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000071041:Esophageal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005764:Gastroesophageal Reflux / Q000150:complications*; D005786:Gene Expression Regulation; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity; D008679:Metaplasia; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D012333:RNA, Messenger; D014157:Transcription Factors; D005999:Glycochenodeoxycholic Acid; C509186:TERT protein, human; D019098:Telomerase; D006851:Hydrochloric Acid
Barrett's metaplasia; GERD; biphenotypic; reprogramming; transcommitment