Skip to main content

Advertisement

SpringerLink
Log in

Origins of Metaplasia in Barrett’s Esophagus: Is this an Esophageal Stem or Progenitor Cell Disease?

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The incidence of esophageal adenocarcinoma has been increasing in Western countries over the past several decades. Though Barrett’s esophagus, in which the normal esophageal squamous epithelium is replaced with metaplastic intestinalized columnar cells due to chronic damage from gastroesophageal reflux, is accepted as the requisite precursor lesion for esophageal adenocarcinoma, the Barrett’s esophagus cell of origin and the molecular mechanism underlying esophageal epithelial metaplasia remain controversial. Much effort has been dedicated towards identifying the Barrett’s esophagus cell of origin since this could lead to more effective prevention and treatment strategies for both Barrett’s esophagus and esophageal adenocarcinoma. Previously, it was hypothesized that terminally differentiated esophageal squamous cells might undergo direct conversion into specialized intestinal columnar cells via the process of transdifferentiation. However, there is increasing evidence that stem and/or progenitor cells are molecularly reprogrammed through the process of transcommitment to differentiate into the columnar cell lineages that characterize Barrett’s esophagus. Given that Barrett’s esophagus originates at the gastroesophageal junction, the boundary between the distal esophagus and gastric cardia, potential sources of these stem and/or progenitor cells include columnar cells from the squamocolumnar junction or neighboring gastric cardia, native esophageal squamous cells, native esophageal cuboidal or columnar cells from submucosal glands or ducts, or circulating bone marrow-derived cells. In this review, we focus on native esophageal specific stem and/or progenitor cells and detail molecular mediators of transcommitment based on recent insights gained from novel mouse models and clinical observations from patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

GERD:

Gastroesophageal reflux disease

GEJ:

Gastroesophageal junction

SCJ:

Squamocolumnar junction

MLE:

Multilayered epithelium

CK:

Cytokeratin

GFP:

Green fluorescent protein

CD:

Cluster of differentiation

BRDU:

5-Bromo-2′-deoxyuridine

LRC:

Label retaining cell

3D:

Three dimensional

RFA:

Radiofrequency ablation

EdU:

5-Ethynyl-2′-deoxyuridine

EGF:

Epidermal growth factor

References

  1. Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med.. 2014;371:2499–2509.

    Article  PubMed  CAS  Google Scholar 

  2. Spechler SJ, Souza RF. Barrett’s esophagus. N Engl J Med.. 2014;371:836–845.

    Article  PubMed  CAS  Google Scholar 

  3. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology.. 2011;140:e18–e52. (quiz e13).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Solaymani-Dodaran M, Logan RF, West J, Card T, Coupland C. Risk of oesophageal cancer in Barrett’s oesophagus and gastro-oesophageal reflux. Gut.. 2004;53:1070–1074.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Spechler SJ, Fitzgerald RC, Prasad GA, Wang KK. History, molecular mechanisms, and endoscopic treatment of Barrett’s esophagus. Gastroenterology.. 2010;138:854–869.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xian W, Ho KY, Crum CP, McKeon F. Cellular origin of Barrett’s esophagus: controversy and therapeutic implications. Gastroenterology.. 2012;142:1424–1430.

    Article  PubMed  Google Scholar 

  7. Eberhard D, Tosh D. Transdifferentiation and metaplasia as a paradigm for understanding development and disease. Cell Mol Life Sci.. 2008;65:33–40.

    Article  PubMed  CAS  Google Scholar 

  8. Wang DH, Souza RF. Transcommitment: paving the way to Barrett’s metaplasia. Adv Exp Med Biol.. 2016;908:183–212.

    Article  PubMed  Google Scholar 

  9. Stairs DB, Nakagawa H, Klein-Szanto A, et al. Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett’s esophagus. PLoS One.. 2008;3:e3534.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Gillen P, Keeling P, Byrne PJ, West AB, Hennessy TP. Experimental columnar metaplasia in the canine oesophagus. Br J Surg.. 1988;75:113–115.

    Article  PubMed  CAS  Google Scholar 

  11. Sarosi 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;21:43–50.

    Article  PubMed  CAS  Google Scholar 

  12. Quante M, Bhagat G, Abrams JA, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of barrett-like metaplasia. Cancer Cell.. 2012;21:36–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Wang X, Ouyang H, Yamamoto Y, et al. Residual embryonic cells as precursors of a Barrett’s-like metaplasia. Cell.. 2011;145:1023–1035.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Oberg S, Johansson J, Wenner J, Walther B. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann Surg.. 2002;235:338–345.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hutchinson 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;20:11–17.

    Article  PubMed  CAS  Google Scholar 

  16. Shields HM, Zwas F, Antonioli DA, Doos WG, Kim S, Spechler SJ. Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett’s epithelium. Dig Dis Sci.. 1993;38:97–108.

    Article  PubMed  CAS  Google Scholar 

  17. Boch JA, Shields HM, Antonioli DA, Zwas F, Sawhney RA, Trier JS. Distribution of cytokeratin markers in Barrett’s specialized columnar epithelium. Gastroenterology.. 1997;112:760–765.

    Article  PubMed  CAS  Google Scholar 

  18. Chen X, Qin R, Liu B, et al. Multilayered epithelium in a rat model and human Barrett’s esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol.. 2008;8:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yu WY, Slack JM, Tosh D. Conversion of columnar to stratified squamous epithelium in the developing mouse oesophagus. Dev Biol.. 2005;284:157–170.

    Article  PubMed  CAS  Google Scholar 

  20. Epperly MW, Guo H, Shen H, et al. Bone marrow origin of cells with capacity for homing and differentiation to esophageal squamous epithelium. Radiat Res.. 2004;162:233–240.

    Article  PubMed  CAS  Google Scholar 

  21. Kalabis J, Oyama K, Okawa T, et al. A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J Clin Investig.. 2008;118:3860–3869.

    PubMed  CAS  Google Scholar 

  22. Epperly MW, Shen H, Jefferson M, Greenberger JS. In vitro differentiation capacity of esophageal progenitor cells with capacity for homing and repopulation of the ionizing irradiation-damaged esophagus. Vivo.. 2004;18:675–685.

    Google Scholar 

  23. DeWard AD, Cramer J, Lagasse E. Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep.. 2014;9:701–711.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Croagh D, Phillips WA, Redvers R, Thomas RJ, Kaur P. Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers. Stem Cells.. 2007;25:313–318.

    Article  PubMed  CAS  Google Scholar 

  25. Doupe DP, Alcolea MP, Roshan A, et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science.. 2012;337:1091–1093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Giroux V, Lento AA, Islam M, et al. Long-lived keratin 15 + esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Investig.. 2017;127:2378–2391.

    Article  PubMed  Google Scholar 

  27. Barbera M, di Pietro M, Walker E, et al. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut.. 2015;64:11–19.

    Article  PubMed  Google Scholar 

  28. Seery JP, Watt FM. Asymmetric stem-cell divisions define the architecture of human oesophageal epithelium. Curr Biol. 2000;10:1447–1450.

    Article  PubMed  CAS  Google Scholar 

  29. Jeong Y, Rhee H, Martin S, et al. Identification and genetic manipulation of human and mouse oesophageal stem cells. Gut.. 2016;65:1077–1086.

    Article  PubMed  CAS  Google Scholar 

  30. Jiang M, Li H, Zhang Y, et al. Transitional basal cells at the squamous-columnar junction generate Barrett’s oesophagus. Nature.. 2017;550:529–533.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Garman KS, Kruger L, Thomas S, et al. Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma. Histopathology.. 2015;67:771–782.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Garman KS. Origin of Barrett’s epithelium: esophageal submucosal glands. Cell Mol Gastroenterol Hepatol.. 2017;4:153–156.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Coad RA, Woodman AC, Warner PJ, Barr H, Wright NA, Shepherd NA. 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;206:388–394.

    Article  PubMed  Google Scholar 

  34. Leedham SJ, Preston SL, McDonald SA, et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett’s oesophagus. Gut.. 2008;57:1041–1048.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. von Furstenberg RJ, Li J, Stolarchuk C, et al. Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation. Cell Mol Gastroenterol Hepatol. 2017;4:385–404.

    Article  Google Scholar 

  36. Yamamoto Y, Wang X, Bertrand D, et al. Mutational spectrum of Barrett’s stem cells suggests paths to initiation of a precancerous lesion. Nat Commun.. 2016;7:10380.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Que J, Okubo T, Goldenring JR, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development.. 2007;134:2521–2531.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Blache P, van de Wetering M, Duluc I, et al. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol.. 2004;166:37–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Clemons NJ, Wang DH, Croagh D, et al. Sox9 drives columnar differentiation of esophageal squamous epithelium: a possible role in the pathogenesis of Barrett’s esophagus. Am J Physiol Gastrointest Liver Physiol.. 2012;303:G1335–G1346.

    Article  PubMed  CAS  Google Scholar 

  40. Wang DH, Clemons NJ, Miyashita T, et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology.. 2010;138:1810–1822.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature.. 1997;386:84–87.

    Article  PubMed  CAS  Google Scholar 

  42. Kong J, Crissey MA, Funakoshi S, Kreindler JL, Lynch JP. Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett’s esophagus. PLoS One.. 2011;6:e18280.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wang DH, Tiwari A, Kim ME, et al. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J Clin Investig.. 2014;124:3767–3780.

    Article  PubMed  CAS  Google Scholar 

  44. Tamagawa Y, Ishimura N, Uno G, Yuki T, Kazumori H, Ishihara S, Amano Y, and Kinoshita Y. Notch signaling pathway and Cdx2 expression in the development of Barrett’s esophagus. Lab Invest. 2012;92:896–909.

    Article  PubMed  CAS  Google Scholar 

  45. Tamagawa Y, Ishimura N, Uno G, et al. Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett’s esophagus. Lab Invest.. 2016;96:325–337.

    Article  PubMed  CAS  Google Scholar 

  46. Menke V, van Es JH, de Lau W, et al. Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by gamma-secretase inhibition. Dis Model Mech.. 2010;3:104–110.

    Article  PubMed  CAS  Google Scholar 

  47. Vega ME, Giroux V, Natsuizaka M, et al. Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett’s-like metaplasia via KLF4. Cell Cycle.. 2014;13:3857–3866.

    Article  PubMed  CAS  Google Scholar 

  48. Colleypriest BJ, Burke ZD, Griffiths LP, et al. Hnf4alpha is a key gene that can generate columnar metaplasia in oesophageal epithelium. Differentiation.. 2017;93:39–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work was supported by the U.S. National Institutes of Health, R01 DK097340 to DHW.

Author information

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, Esophageal Diseases Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 8584, Dallas, TX, 75390-8584, USA

    Wei Zhang & David H. Wang

  2. Medical Service, Dallas VA Medical Center, Dallas, TX, USA

    David H. Wang

Authors
  1. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Drafting of the manuscript (WZ and DHW), critical revision of the manuscript for intellectual content (WZ and DHW), obtained funding (DHW).

Corresponding author

Correspondence to David H. Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Wang, D.H. Origins of Metaplasia in Barrett’s Esophagus: Is this an Esophageal Stem or Progenitor Cell Disease?. Dig Dis Sci 63, 2005–2012 (2018). https://doi.org/10.1007/s10620-018-5069-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-018-5069-5

Keywords

Search

Navigation