Pathogenesis and Cells of Origin of Barrett's Esophagus

In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications. In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin, including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophagogastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications. In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa containing epithelial cells with gastric and intestinal features replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD) (Figure 1).1Spechler S.J. Souza R.F. Barrett’s esophagus.N Engl J Med. 2014; 371: 836-845Crossref PubMed Scopus (333) Google Scholar, 2Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus.Am J Gastroenterol. 2016; 111: 30-50Crossref PubMed Scopus (970) Google Scholar, 3Hayeck T.J. Kong C.Y. Spechler S.J. et al.The prevalence of Barrett’s esophagus in the US: estimates from a simulation model confirmed by SEER data.Dis Esoph. 2010; 23: 451-457Crossref PubMed Scopus (129) Google Scholar, 4Thrift A.P. Barrett's esophagus and esophageal adenocarcinoma: how common are they really?.Dig Dis Sci. 2018; 63: 1988-1996Crossref PubMed Scopus (52) Google Scholar US guidelines state that a diagnosis of BE requires endoscopic identification of columnar mucosa extending at least 1 cm proximal to the esophagogastric junction (EGJ) and histologic confirmation that the columnar mucosa is intestinal-type.2Shaheen N.J. Falk G.W. Iyer P.G. et al.ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus.Am J Gastroenterol. 2016; 111: 30-50Crossref PubMed Scopus (970) Google Scholar, 3Hayeck T.J. Kong C.Y. Spechler S.J. et al.The prevalence of Barrett’s esophagus in the US: estimates from a simulation model confirmed by SEER data.Dis Esoph. 2010; 23: 451-457Crossref PubMed Scopus (129) Google Scholar, 4Thrift A.P. Barrett's esophagus and esophageal adenocarcinoma: how common are they really?.Dig Dis Sci. 2018; 63: 1988-1996Crossref PubMed Scopus (52) Google Scholar There is no consensus on the precise definition of the term metaplasia, which was first used by Rudolf Virchow in 1884 to describe normal tissue in an abnormal location.5Virchow R. Ueber metaplasie: Vortrag, gehalten auf dem internationalen medicinischen Congress in Kopenhagen.Virchows Arch. 1884; 97: 410-430Crossref Scopus (24) Google Scholar Today, many types of metaplastic tissue, including BE, are not considered normal but pathologic because they are precursors to cancer. Cell biologists have often defined metaplasia as the conversion of 1 differentiated cell type into another, but Slack et al6Tosh D. Slack J.M. How cells change their phenotype.Nat Rev Mol Cell Biol. 2002; 3: 187-194Crossref PubMed Scopus (361) Google Scholar, 7Slack J.M. Metaplasia and transdifferentiation: from pure biology to the clinic.Nat Rev Mol Cell Biol. 2007; 8 (369–278)Crossref Scopus (184) Google Scholar have argued that it is better to define metaplasia as the conversion of one tissue type into another, noting that metaplastic tissues comprise multiple disparate types of differentiated cells. Metaplasias usually develop in patients with chronic tissue injury, and it is widely accepted that the pathogenesis of BE begins with chronic esophageal injury caused by GERD. However, it is not clear how columnar mucosa replaces GERD-damaged squamous mucosa. We review potential mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin for Barrett’s metaplasia—hypotheses are not mutually exclusive and there could be more than 1 type of BE progenitor cell. We discuss the concept of metaplasia as an initial wound healing response and clinical implications. 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).8Wang D.H. The esophageal squamous epithelial cell-still a reasonable candidate for the Barrett's esophagus cell of origin?.Cell Mol Gastroenterol Hepatol. 2017; 4: 157-160Abstract Full Text Full Text PDF PubMed Google Scholar Although differentiated cells once were considered immutable, studies have demonstrated that differentiated cells can be reprogrammed to acquire characteristics of immature progenitor cells.9Takahashi K. Tanabe K. Ohnuki M. et al.Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (15017) Google Scholar Many types of mature cells have the capacity to dedifferentiate into cells with progenitor cell characteristics.10Mills J.C. Sansom O.J. Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract.Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar Transdifferentiation in the esophagus therefore might occur via a 2-stage process of GERD-induced reprogramming in which mature squamous cells reverse their differentiation to acquire progenitor cell-like plasticity before changing to a columnar phenotype. Although it is conceivable that a squamous cell might change its phenotype without first de-differentiating (by simultaneously down-regulating its squamous genetic program while up-regulating a columnar genetic program), it is not clear that such a process occurs naturally in adult tissues.11Jopling C. Boue S. Izpisua Belmonte J.C. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration.Nat Rev Mol Cell Biol. 2011; 12: 79-89Crossref PubMed Scopus (461) Google Scholar In the fundus of mouse stomach injured by infection with Helicobacter pylori or by drugs toxic to parietal cells, the death of parietal cells appears to be accompanied by transdifferentiation of chief cells into proliferative cells that expresses trefoil factor 2 (TFF2, also known as spasmolytic polypeptide).12Goldenring J.R. Nam K.T. Oxyntic atrophy, metaplasia, and gastric cancer.Prog Mol Biol Transl Sci. 2010; 96: 117-131Crossref PubMed Scopus (45) Google Scholar, 13Goldenring J.R. Nam K.T. Mills J.C. The origin of pre-neoplastic metaplasia in the stomach: chief cells emerge from the Mist.Exp Cell Res. 2011; 317: 2759-2764Crossref PubMed Scopus (68) Google Scholar, 14Radyk M.D. Burclaff J. Willet S.G. et al.Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells.Gastroenterology. 2018; 154: 839-843Abstract Full Text Full Text PDF PubMed Google Scholar, 15Sáenz J.B. Mills J.C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer.Nat Rev Gastroenterol Hepatol. 2018; 15: 257-273Crossref PubMed Scopus (64) Google Scholar In mice with acute injury, there is evidence that development of spasmolytic polypeptide-expressing metaplasia (SPEM) occurs when mature chief cells dedifferentiate and re-enter the cell cycle. This is a 3-stage process during which the cells shut down mTORC1 signaling, which enables autophagy to recycle cellular material for use in the synthesis of new cell structures; begin to express genes associated with metaplasia, such as SOX9 and TFF2; and then reactivate mTORC1 signaling, which enables them to re-enter the cell cycle.16Willet S.G. Lewis M.A. Miao Z.F. et al.Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.EMBO J. 2018; 37 (pii: e98311)Crossref PubMed Scopus (87) Google Scholar Mills and colleagues16Willet S.G. Lewis M.A. Miao Z.F. et al.Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.EMBO J. 2018; 37 (pii: e98311)Crossref PubMed Scopus (87) Google Scholar coined the term paligenosis (from the Greek for “return to the regenerative state”) for this process, which appears to be a conserved function of many cell types. Conceivably, paligenosis in esophageal squamous cells could result in their transdifferentiation into BE metaplastic cells, or into SPEM-like cells that could transition to BE metaplasia through further paligenotic events.17Jin R.U. Mills J.C. Are gastric and esophageal metaplasia relatives? the case for Barrett's stemming from SPEM.Dig Dis Sci. 2018; 63: 2028-2041Crossref PubMed Scopus (0) Google Scholar Through paligenosis, mature cells dedifferentiate and re-enter the cell cycle to repair injured tissues either by regenerating more normal tissue, or by transdifferentiating into a metaplastic tissue that might be more resistant to whatever noxious factor is inducing the chronic injury (GERD in the esophagus). With repeated cycles of injury and repair in chronic inflammatory conditions, cells could undergo multiple rounds of paligenotic dedifferentiation and redifferentiation cycles, progressively acquiring mutations through replicative stress.15Sáenz J.B. Mills J.C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer.Nat Rev Gastroenterol Hepatol. 2018; 15: 257-273Crossref PubMed Scopus (64) Google Scholar Those mutations might be retained without consequence in quiescent, redifferentiated cells. When the mutated cells re-enter the cell cycle with a subsequent injury, however, they might acquire further mutations that eventually block redifferentiation, leading to clonal expansion and carcinogenesis. This has been called the cyclical hit model of tumorigenesis.15Sáenz J.B. Mills J.C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer.Nat Rev Gastroenterol Hepatol. 2018; 15: 257-273Crossref PubMed Scopus (64) Google Scholar If metaplastic tissues develop through transdifferentiation, they might undergo multiple cyclical hits, which increase their potential for transformation. There are no data to directly support the model in which BE develops through transdifferentiation of mature squamous cells. Lineage-tracing studies in mice have not identified such transdifferentiation as a likely etiology for a columnar-lined esophagus.18Jiang M. Li H. Zhang Y. et al.Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.Nature. 2017; 550: 529-533Crossref PubMed Scopus (127) Google Scholar Even in mouse stomach, in which there is strong evidence that acute injury results in transdifferentiation of chief cells into SPEM, there is evidence for an alternative mechanism, in which SPEM develops and persists through the abnormal differentiation of stem cells in the isthmus of gastric glands.19Hayakawa Y. Fox J.G. Wang T.C. Isthmus stem cells are the origins of metaplasia in the gastric corpus.Cell Mol Gastroenterol Hepatol. 2017; 4: 89-94Abstract Full Text Full Text PDF PubMed Google Scholar It is also difficult to reconcile the concept of BE development through transdifferentiation with the observation that Barrett’s metaplasia persists even when the GERD that might initiate transdifferentiation through paligenosis is controlled by medical or surgical treatment. Mucosa comprising exclusively uninjured, transdifferentiated cells that have exited the cell cycle could not maintain the multiple cell types present in Barrett’s metaplasia. Although it could be possible that paligenotic dedifferentiation confers stem cell-like self-renewal abilities in addition to the plasticity leading to transdifferentiation, there is no evidence from experiments for this concept. Persistence of BE in the absence of reflux esophagitis is more readily explained by metaplasia developing from reprogramming of an extant stem-like progenitor cell, which is the process of 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.20Wang D.H. Souza R.F. Transcommitment: paving the way to Barrett's metaplasia.Adv Exp Med Biol. 2016; 908: 183-212Crossref PubMed Scopus (18) Google Scholar 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 differentiate abnormally, presumably due to abnormal environmental factors like GERD. The development of Barrett’s metaplasia from reprogrammed (transcommitted) progenitor cells could readily account for the different cell types and their persistence even when GERD is controlled. We do not know which progenitor cells give rise to Barrett’s metaplasia, but there are 4 categories of candidates (Figure 2). These include progenitor cells native to the esophagus, including basal cells of the squamous epithelium or cells of esophageal submucosal glands (ESMGs) and their ducts; progenitor cells native to the proximal stomach (the gastric cardia) that migrate into the esophagus to repair reflux-damaged squamous epithelium; specialized populations of cells at the EGJ that migrate into the esophagus to replace reflux-damaged squamous epithelium; and bone marrow progenitor cells transported through the blood to the esophagus to replace reflux-damaged squamous epithelium (see Table 1).Table 1Proposed Progenitor Cells and Studies Supporting Their Participation in Barrett’s Esophagus PathogenesisModelHuman or animalStudy findingsFirst author, yearEsophageal squamous epithelium Biopsy tissueHumanScanning electron micrographs of biopsies at the squamous–BE junction revealed a distinct cell with squamous and columnar features.Shields, 199340Shields H.M. Zwas F. Antonioli D.A. et al.Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett's epithelium.Dig Dis Sci. 1993; 38: 97-108Crossref PubMed Scopus (84) Google ScholarSawhney, 199641Sawhney R.A. Shields H.M. Allan C.H. et al.Morphological characterization of the squamocolumnar junction of the esophagus in patients with and without Barrett's epithelium.Dig Dis Sci. 1996; 41: 1088-1098Crossref PubMed Scopus (38) Google Scholar Reflux esophagitis induced by esophagojejunostomyRatEsophagojejunostomy resulted in esophageal ulceration with squamous cells at the proximal ulcer edges showing decreased SOX2 (squamous cell gene) and increased SOX9 (columnar cell gene). Distally, however, columnar-lined esophagus developed through proximal migration of jejunal cells in a wound-healing response.Agoston, 201842Agoston A.T. Pham T.H. Odze R.D. et al.Columnar-lined esophagus develops via wound repair in a surgical model of reflux esophagitis.Cell Mol Gastroenterol Hepatol. 2018; 6: 389-404Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Cell cultureHumanNES-B3T and NES-B10T cells(telomerase-immortalized esophageal squamous cell lines from patients with BE)Exposure to acid, bile salts, or nitric oxide resulted in decreased expression of squamous cell factors (p63, SOX2), increased expression of columnar cell factors (SOX9, CDX2, FOXA2), and activation of upstream signaling pathways (Hedgehog, BMP4).Long-term exposure (more than 30 wk) of NES-B10T to acid and bile salts caused columnar cell-like morphologic changes.Asanuma, 201643Asanuma K. Huo X. Agoston A. et al.In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression.Gut. 2016; 65: 1416-1426Crossref PubMed Scopus (17) Google ScholarMinacapelli, 201744Minacapelli C.D. Bajpai M. Geng X. et al.Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux.Am J Physiol Gastrointest Liver Physiol. 2017; 312: G615-G622Crossref PubMed Scopus (18) Google ScholarWang, 201446Wang D.H. Tiwari A. Kim M.E. et al.Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia.J Clin Invest. 2014; 124: 3767-3780Crossref PubMed Scopus (67) Google Scholar Cell cultureHumanHET-1A cells(SV40 transfected human esophageal cells)Cells treated with BMP4 or transfected with constitutively active BMPR1A showed up-regulated SOX9 expression.Wang, 201045Wang D.H. Clemons N.J. Miyashita T. et al.Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia.Gastroenterology. 2010; 138: 1810-1822Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Cell cultureHumanPrimary culture of esophageal cells from patients without Barrett’s or esophagitisExposure to acid and bile salts increased BMP4 expression. Treatment with BMP4 increased CDX2 protein expression.Zhou, 200947Zhou G. Sun Y.G. Wang H.B. et al.Acid and bile salt up-regulate BMP4 expression in human esophageal epithelium cells.Scand J Gastroenterol. 2009; 44: 926-932Crossref PubMed Scopus (22) Google ScholarESMGs Esophagectomy and autopsy tissueHumanEsophagectomy and autopsy specimens show ESMGs associated with both squamous islands and areas of Barrett’s metaplasia. ESMGs can express Krt7, P63 and SOX9, and ESMGs associated with Barrett’s metaplasia can demonstrate necrotizing sialometaplasia-like change/acinar ductal metaplasia.Coad, 200553Coad R.A. Woodman A.C. Warner P.J. et al.On the histogenesis of Barrett's oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts.J Pathol. 2005; 206: 388-394Crossref PubMed Scopus (69) Google ScholarBraxton, 201458Braxton D.R. Nickleach D.C. Liu Y. et al.Necrotizing sialometaplasia-like change of the esophageal submucosal glands is associated with Barrett's esophagus.Virchows Arch. 2014; 465: 135-143Crossref PubMed Google ScholarGarman, 201559Garman K.S. Kruger L. Thomas S. et al.Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.Histopathology. 2015; 67: 771-7782Crossref PubMed Scopus (15) Google ScholarGonzalez, 201660Gonzalez G. Huang Q. Mashimo H. Characterization of oncocytes in deep esophageal glands.Dis Esophagus. 2016; 29: 670-680Crossref PubMed Scopus (8) Google Scholar Esophagectomy and biopsy tissue, genomic assessment used for clonality studiesHumanIn some patients with BE, ESMGs and their ducts share p16/CDKN2A mutations with overlying Barrett’s metaplasia, and a patient has been described with shared mitochondrial DNA mutations in both squamous and Barrett’s epithelium suggesting that ESMGs harbor plastic progenitor cells that can give rise either to squamous or BE.Paulson, 200654Paulson T.G. Xu L. Sanchez C. et al.Neosquamous epithelium does not typically arise from Barrett's epithelium.Clin Cancer Res. 2006; 12: 1701-1706Crossref PubMed Scopus (41) Google ScholarLeedham, 200856Leedham S.J. Preston S.L. McDonald S.A. et al.Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus.Gut. 2008; 57: 1041-1048Crossref PubMed Scopus (171) Google ScholarNicholson, 201255Nicholson A.M. Graham T.A. Simpson A. et al.Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor.Gut. 2012; 61: 1380-1389Crossref PubMed Scopus (62) Google Scholar Rings of esophageal epithelium excised, reflux esophagitis induced by cardioplasty and pentagastrin administrationCanineColumnar-lined esophagus developed above ESMGs. Proliferation in ESMGs and ducts increased with surgically induced reflux.Gillen, 198861Gillen P. Keeling P. Byrne P.J. et al.Experimental columnar metaplasia in the canine oesophagus.Br J Surg. 1988; 75: 113-115Crossref PubMed Google ScholarLi, 199462Li H. Walsh T.N. O'Dowd G. et al.Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus.Surgery. 1994; 115: 176-181PubMed Google Scholarvan Nieuwenhove, 199863Van Nieuwenhove Y. Willems G. Gastroesophageal reflux triggers proliferative activity of the submucosal glands in the canine esophagus.Dis Esophagus. 1998; 11: 89-93Crossref PubMed Scopus (21) Google Scholar Esophageal injury by radiofrequency ablationPorcineAblation injury was associated with ESMG proliferation, acinar ductal metaplasia, and increased SOX9 and KRT7 expression in ESMGs.Kruger, 201764Krüger L. Gonzalez L.M. Pridgen T.A. et al.Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair.Am J Physiol Gastrointest Liver Physiol. 2017; 313: G180-G191Crossref PubMed Scopus (25) Google Scholar 3-Dimensional culture of ESMG cellsPorcineESMG cells grown in 3-dimensional culture produce 2 distinct phenotypes of spheroids: 1 solid with squamous markers (p63) and 1 hollow with BE markers (KRT7).von Furstenberg, 201765von Furstenberg R. Li J. Stolarchuk C. et al.Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation.Cell Mol Gastroenterol Hepatol. 2017; 4: 385-404Abstract Full Text Full Text PDF PubMed Google ScholarGastric cardiac mucosa Transgenic mice (mixed 129/SvEv and C57BL/6 background) with inflammation induced by esophageal IL1B expression, with lineage-tracing and 3-dimensional cell cultureMouseGastric cardiac mucosa expands and contributes to Barrett’s-like changes at the SCJ. Bile acid and hypergastrinemia promote metaplasia and dysplasia.Quante, 201268Quante M. Bhagat G. Abrams J.A. et al.Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.Cancer Cell. 2012; 21: 36-51Abstract Full Text Full Text PDF PubMed Scopus (336) Google ScholarLee, 201772Lee Y. Urbanska A.M. Hayakawa Y. et al.Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus.Oncotarget. 2017; 8: 203-214Crossref PubMed Scopus (0) Google Scholar Specialized populations of cells at the EGJ: RECs Transgenic mice (mixed 129/SvEv and C57BL/6 background) with inflammation induced by esophageal diphtheria toxin expression, and mice with p63 deletion (lineage tracing not used)MouseA normally quiescent population of RECs (p63-negative, CAR4+, KRT7+) at the EGJ contributes to Barrett’s-like changes in embryos with p63 deletion and in adults with diphtheria toxin-induced squamous cell injury.Wang, 201173Wang X. Ouyang H. Yamamoto Y. et al.Residual embryonic cells as precursors of a Barrett's-like metaplasia.Cell. 2011; 145: 1023-1035Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar Specialized populations of cells at the EGJ: TBCs Cell culture, esophagoduodenal anastomosis and genetic mouse models (mixed 129/SvEv and C57BL/6 background) with lineage tracingMouse and humanTransitional basal cells (KRT5+, p63+, KRT7+) at the EJG contribute to Barrett’s-like changes in 3-dimensional organoids and at the SCJ.Jiang, 201718Jiang M. Li H. Zhang Y. et al.Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.Nature. 2017; 550: 529-533Crossref PubMed Scopus (127) Google ScholarCirculating bone marrow cells Transplantation of bone marrow from male rats to female rats, followed by esophago-jejunostomy to produce columnar-lined esophagusRatY chromosome found in epithelial cells of columnar-lined esophagus of female rats.Sarosi, 200882Sarosi G. Brown G. Jaiswal K. et al.Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett’s esophagus.Dis Esophagus. 2008; 21: 43-50Crossref PubMed Scopus (130) Google Scholar Transplant of β-galactosidase-expressing bone marrow cells, followed by esophagojejunostomy to produce columnar-lined esophagusMouseβ-galactosidase-expressing epithelial cells found in columnar-lined esophagus.Hutchinson, 201183Hutchinson L. Stenstrom B. Chen D. et al.Human Barrett's adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant.Stem Cells Dev. 2011; 20: 11-17Crossref PubMed Scopus (67) Google Scholar Case report of a male patient who received a bone marrow transplant from a femaleHumanPatient later developed an esophageal tumor with cells containing 2 X and no Y chromosomesHutchinson, 201183Hutchinson L. Stenstrom B. Chen D. et al.Human Barrett's adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant.Stem Cells Dev. 2011; 20: 11-17Crossref PubMed Scopus (67) Google Scholar Open table in a new tab Because the intestinal-type cells that characterize Barrett’s metaplasia are not normally found in the esophagus, stomach, or bone marrow, reprogramming would be required for any of these progenitor cell candidates to give rise to Barrett’s metaplasia. GERD is presumed to be the factor that induces the reprogramming needed for the transcommitment of these progenitor cells. It is important to note that hypotheses about the cell of origin are not mutually exclusive—there could be more than 1 type of Barrett’s progenitor cell. Furthermore, in addition to giving rise to BE initially, any of these potential progenitor cells might give rise to the recurrences of Barrett’s metaplasia that can develop months to years after initially successful endoscopic eradication therapy.21Guthikonda A. Cotton C.C. Madanick R.D. et al.Clinical outcomes following recurrence of intestinal metaplasia after successful treatment of Barrett's esophagus with radiofrequency ablation.Am J Gastroenterol. 2017; 112: 87-94Crossref PubMed Scopus (45) Google Scholar During injury and repair, tissues often reactivate early developmental signaling pathways. Progenitor cells in an adult organ are assumed to retain the genotype of the more primitive embryonic progenitor cells from which they arose.22Shen C.N. Burke Z.D. Tosh D. Transdifferentiation, metaplasia and tissue regeneration.Organogenesis. 2004; 1: 36-44Crossref PubMed Scopus (56) Google Scholar Consequently, if metaplasias develop from GERD-induced reprogramming of progenitor cells in adult organs, the new cell types that develop are likely to reflect the differentiation potential of those embryonic progenitor cells. It is therefore important to consider the embryologic development of the esophagus and stomach. The esophagus and stomach develop from the foregut portion of the primitive endodermal digestive tube.23Johns B.A.E. Developmental changes in the oesophageal epithelium in man.J Anat. 1952; 86: 431-439PubMed Google Scholar, 24DeNardi F.G. Riddell R.H. The normal esophagus.Am J Surg Pathol. 1991; 15: 296-309Crossref PubMed Google Scholar, 25De Hertogh G. Van Eyken P. Ectors N. et al.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. 2005; 11: 4490-4496Crossref PubMed Scopus (16) Google Scholar The respiratory tube that gives rise to the trachea and lungs forms as an outgrowth of the digestive tube, separating from it at around 4 weeks of gestation in humans and during embryonic days 9.5–11.5 in mice.26Que J. 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. 2015; 4: 419-430Crossref PubMed Google Scholar In mice, multiple signaling pathways (such as those involving SHH, BMP, and WNT) and transcription factors (such as SOX2 and FOXF1) mediate this separation process.27Litingtung Y. Lei L. Westphal H. et al.Sonic hedgehog is essential to foregut development.Nat Genet. 1998; 20: 58-61Crossref PubMed Scopus (573) Google Scholar, 28Que J. Choi M. Ziel J.W. et al.Morphogenesis