Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyPathogenesis and Cells of Origin of Barrett's Esophagus
Section snippets
Transdifferentiation
A potential mechanism of BE pathogenesis involves transdifferentiation, in which fully differentiated esophageal squamous cells change into fully differentiated columnar cells—either directly (without undergoing a cell division) or indirectly (via cell division).8 Although differentiated cells once were considered immutable, studies have demonstrated that differentiated cells can be reprogrammed to acquire characteristics of immature progenitor cells.9 Many types of mature cells have the
Transcommitment
Transcommitment is the process in which immature progenitor cells that are able to proliferate and differentiate into different cell types are reprogrammed to alter their normal pattern of differentiation.20 Transcommitment shares late features of transdifferentiation through paligenosis, a process that starts with dedifferentiation of mature cells into progenitor-like cells before they re-differentiate abnormally. In contrast, transcommitment starts with immature progenitor cells that
Could Cells Native to the Esophagus Provide Barrett’s Esophagus Progenitor Cells?
There are several lines of evidence that could support either transdifferentiation of esophageal squamous cells, through paligenosis, or transcommitment of esophageal progenitor cells in the pathogenesis of Barrett’s metaplasia. For example, scanning electron microscopy of biopsy specimens taken from the junction between squamous and Barrett’s epithelium revealed a distinct cell type, with prominent intercellular ridges (a feature of squamous cells) and microvilli (a feature of columnar cells).
Stomach Cells as Barrett’s Esophagus Progenitor Cells
Although Barrett’s metaplasia is considered intestinal because it contains goblet cells and expresses some intestinal markers, it also contains gastric-type cells that express gastric proteins, such as claudin18 and TFF2.66, 67 Quante et al68 found that Lgr5+ epithelial progenitor cells in the gastric cardia might be cells of origin for Barrett’s-like metaplasia in mice with chronic inflammation in the esophagus and forestomach. In these mice, an Epstein-Barr virus promoter (ED-L2) promotes
Barrett’s Metaplasia as a Wound-Healing Process
Regardless of which progenitor cells give rise to BE, the metaplastic process is assumed to be initiated by esophageal injury from GERD. Reflux esophagitis often leads to esophageal ulceration that is bordered proximally by squamous epithelium and distally by gastric epithelium, with ESMGs and their ducts lying underneath the ulcer crater. Cells from any of these locations might contribute to esophageal re-epithelization initially via a wound healing process, with GERD-induced reprogramming
Cardiac Mucosa, Intestinal Metaplasia With Goblet Cells, and Barrett’s Esophagus
The gastric cardia is believed to be lined, to a variable extent, by cardiac mucosa—a glandular lining comprising mucus-secreting, gastric foveolar-type cells with no goblet cells and few or no parietal cells (Figure 5). However, there is considerable indirect evidence to support a hypothesis, proposed by Chandrasoma88 in 1997, that cardiac mucosa is not normal but an acquired, GERD-induced metaplasia, and that cardiac mucosa is the precursor of intestinal metaplasia in BE.89 For example,
Acknowledgments
All authors contributed equally to the preparation of this manuscript.
References (111)
The esophageal squamous epithelial cell-still a reasonable candidate for the Barrett's esophagus cell of origin?
Cell Mol Gastroenterol Hepatol
(2017)- et al.
Induction of pluripotent stem cells from adult human fibroblasts by defined factors
Cell
(2007) - et al.
Oxyntic atrophy, metaplasia, and gastric cancer
Prog Mol Biol Transl Sci
(2010) - et al.
The origin of pre-neoplastic metaplasia in the stomach: chief cells emerge from the Mist
Exp Cell Res
(2011) - et al.
Isthmus stem cells are the origins of metaplasia in the gastric corpus
Cell Mol Gastroenterol Hepatol
(2017) - et al.
Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps
Differentiation
(2006) - et al.
Preparing for the first breath: genetic and cellular mechanisms in lung development
Dev Cell
(2010) - et al.
Development and stem cells of the esophagus
Semin Cell Dev Biol
(2017) - et al.
Conversion of columnar to stratified squamous epithelium in the developing mouse oesophagus
Dev Biol
(2005) - et al.
3D modeling of esophageal development using human PSC-derived basal progenitors reveals a critical role for notch signaling
Cell Stem Cell
(2018)
Columnar-lined esophagus develops via wound repair in a surgical model of reflux esophagitis
Cell Mol Gastroenterol Hepatol
Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation
Cell Mol Gastroenterol Hepatol
Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia
Cancer Cell
Residual embryonic cells as precursors of a Barrett's-like metaplasia
Cell
Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers
BMC Gastroenterol
Prospective evaluation of multilayered epithelium in Barrett's esophagus
Am J Gastroenterol
Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders
Hum Pathol
Immunohistochemical panel for distinguishing esophageal adenocarcinoma from squamous cell carcinoma: a combination of p63, cytokeratin 5/6, MUC5AC, and anterior gradient homolog 2 allows optimal subtyping
Hum Pathol
columnar metaplasia in three types of surgical mouse models of esophageal reflux
Cell Mol Gastroenterol Hepatol
A proposal for a new validated histological definition of the gastroesophageal junction
Hum Pathol
Manifestations of coronary atherosclerosis in young trauma victims—an autopsy study
J Am Coll Cardiol
Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal
Gastroenterology
Effects of dropping the requirement for goblet cells from the diagnosis of Barrett’s esophagus
Clin Gastroenterol Hepatol
Barrett’s esophagus
N Engl J Med
ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus
Am J Gastroenterol
The prevalence of Barrett’s esophagus in the US: estimates from a simulation model confirmed by SEER data
Dis Esoph
Barrett's esophagus and esophageal adenocarcinoma: how common are they really?
Dig Dis Sci
Ueber metaplasie: Vortrag, gehalten auf dem internationalen medicinischen Congress in Kopenhagen
Virchows Arch
How cells change their phenotype
Nat Rev Mol Cell Biol
Metaplasia and transdifferentiation: from pure biology to the clinic
Nat Rev Mol Cell Biol
Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract
Sci Signal
Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration
Nat Rev Mol Cell Biol
Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells
Gastroenterology
Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer
Nat Rev Gastroenterol Hepatol
Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis
EMBO J
Are gastric and esophageal metaplasia relatives? the case for Barrett's stemming from SPEM
Dig Dis Sci
Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus
Nature
Transcommitment: paving the way to Barrett's metaplasia
Adv Exp Med Biol
Clinical outcomes following recurrence of intestinal metaplasia after successful treatment of Barrett's esophagus with radiofrequency ablation
Am J Gastroenterol
Transdifferentiation, metaplasia and tissue regeneration
Organogenesis
Developmental changes in the oesophageal epithelium in man
J Anat
The normal esophagus
Am J Surg Pathol
On the origin of cardiac mucosa: a histological and immunohistochemical study of cytokeratin expression patterns in the developing esophagogastric junction region and stomach
World J Gastroenterol
The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal-esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus
Wiley Interdiscip Rev Dev Biol
Sonic hedgehog is essential to foregut development
Nat Genet
Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations
Development
Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus
Nat Genet
beta-Catenin promotes respiratory progenitor identity in mouse foregut
Proc Natl Acad Sci U S A
Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm
Development
BMP signaling in the development of the mouse esophagus and forestomach
Development
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Conflicts of interest The authors disclose no conflicts.