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Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus

Abstract

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy1,2,3, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown1,2,3. In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells4. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells5,6,7,8. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous–columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous–columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.

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Figure 1: An expanded columnar epithelium consisting of basal and luminal cells at the oesophageal squamous–columnar junction in Krt5CreER;R26Sox2–GFP mutants.
Figure 2: A unique basal progenitor population (p63+KRT7+) maintains the transitional epithelium at the SCJ.
Figure 3: CDX2 overexpression promotes intestinal metaplasia of the transitional basal progenitor cells at the SCJ.
Figure 4: The transitional epithelium is also present in the human SCJ and amplified during Barrett’s oesophagus pathogenesis.

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Acknowledgements

We thank B. Hogan and M. R. Stupnikov for critical reading of the manuscript. This work is partly supported by R01DK113144, R01DK100342, R01HL132996, March of Dimes Research Grant 1-FY14-528 and the Price Family Foundation. This work is also supported by R01CA112403 and R01CA193455 (J.X.), the National Key Research and Development Program of China 2016YFA0502202 (H.W.), National Natural Science Foundation of China 81728001 (J.Q.), 31471121 and 81773394 (H.C.), 81302068 and 81772994 (K.L.), the Program for the Top Young Innovative Talents of Fujian Province and the International Collaborative Project of Fujian Province (project 2017I0014, K.L.).

Author information

Affiliations

Authors

Contributions

M.J. and J.Q. designed experiments, analysed data and wrote the manuscript. M.J. and J.Q. generated the otet-Cdx2 transgenic and Krt7CreER knockin mouse lines. M.J. performed immunostaining, imaging, laser microdissection, flow cytometry, organoid culture and mouse genetics. H.L. performed qPCR and immunostaining. Y.-C.L. and J.Y. generated the CDX2 overexpression plasmid. Y.Z. performed viral work. Y.Y. generated p63-null mutants. K.L., H.Wa. and S.L. assisted with mouse genetics. R.L., X.C. and J.S. performed the acid reflux surgery. X.L., H. Wu, J.Z. and J.S. assisted with imaging. J.X. and D.-K.L. provided the p63CreER mouse line. Z.Z., L.Z., J.A.A., T.C.W., A.R.S., Q.W., H.C. and X.S. provided human MLE and Barrett’s oesophagus samples.

Corresponding author

Correspondence to Jianwen Que.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks C. Blanpain, R. Fitzgerald and T. Sato for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Multiple models have been proposed to explain the cell of origin for Barrett’s oesophagus.

a, Transdifferentiation of the stratified squamous oesophageal epithelium into Barrett’s epithelium. b, Transdifferentiation of circulating bone marrow cells into Barrett’s epithelium. c, Expansion of the oesophageal submucosal gland leads to Barrett’s oesophagus. d, Stem and progenitor cells (Lgr5+) in the cardia mucosa differentiate into Barrett’s oesophagus. e, Expansion of the quiescent RECs at the SCJ leads to Barrett’s oesophagus formation. None of the studies that form the basis of these models recapitulates the pathological changes characteristically associated with Barrett’s oesophagus in humans, such as the presence of intestinal goblet cells.

Extended Data Figure 2 Expansion of the columnar epithelium at the SCJ in Krt5CreER;R26Sox2–GFP mutants.

a, Generation of Krt5CreER;R26Sox2–GFP (SOX2 overexpression) mutants. b, The columnar epithelium secretes mucin, as indicated by Alcian blue and PAS staining. n = 7 per group. c, The mucin-secreting cells (AGR2+) are derived from KRT5+ basal progenitor cells, as verified by the lineage tracing tag GFP. n = 7. d, High magnification image of Fig. 1b to show that expanded GFP+KRT7+ basal progenitor cells invade the underneath of the cardia mucosa on SOX2 overexpression. n = 7. e, High magnification image of Fig. 1c, showing that expanded basal cells (KRT5+) invade and intercalate with the cardia mucosal epithelium (CLDN18+) on SOX2 overexpression. Note that KRT5+ cells (arrow and arrowheads) do not express CLDN18. Conversely, CLDN18+ cells do not express KRT5 (asterisk). n = 7. f, The columnar epithelium does not express the squamous cell marker loricrin. n = 7. White and blue dotted lines indicate the amplified columnar epithelium and the stratified squamous epithelium, respectively. g, Co-staining of X-gal with KRT5 and p63 indicates Lgr5+ cardia progenitor cells do not contribute to KRT5+ or p63+ basal cells in Lgr5CreER;R26LacZ mice with both short-term tracing and long-term tracing. n = 3 per group. Scale bars, 20 μm.

Extended Data Figure 3 Basal progenitor cells contribute to columnar metaplasia following bile acid reflux induced by anastomosis surgery.

a, Oesophageal–duodenal anastomosis and lineage tracing in p63CreER;R26tdTomato mice. b, Metaplasia does not occur at the distal oesophagus, where the anastomosis surgery site is located (arrow). Note that Alcian blue, PAS and CDX2 label the intestinal (but not the squamous) oesophageal epithelium. n = 5. c, Lineage-labelled transitional epithelial cells (tdT+) expand and resemble the MLE, expressing the columnar markers (KRT7, KRT8) and basal cell markers (KRT5 and p63). The expanded epithelium secretes mucin, as indicated by Alcian blue and PAS staining. n = 5. Scale bars, 20 μm.

Extended Data Figure 4 The transitional columnar epithelium is present at the SCJ of normal mice.

a, The transitional epithelium (asterisk) does not express involucrin and loricrin, markers labelling the stratified squamous epithelium. n = 11. b, Basal cells of the transitional epithelium express KRT5 but not the cardia epithelial marker CLDN18. n = 11. c, The KRT7+ transitional basal cells are highly proliferative (Ki67+, arrowheads). n = 3. d, The transitional basal cells of the SCJ express p75, KRT7 and KRT5, but not KRT8. Note that p75 and KRT5 are also expressed in the neighbouring squamous basal cells. n = 5. e, FACS analysis reveals p75+ basal cells include two subpopulations, squamous basal cells (p63+KRT7) and transitional basal cells (p63+KRT7+). n = 3 independent experiments. f, A representative culture of p63+KRT7− and p63+KRT7+ basal progenitor cells. Note that p63+KRT7+ transitional basal cells in the colony are loosely arranged, unlike the cobblestone characteristic of the squamous basal cell colony (p63+KRT7). n = 5 per group. g, p63+KRT7 and p63+KRT7+ basal progenitor cells generate keratinized (Loricrin+KRT7) and non-keratinized (LoricrinKRT7+) epithelium, respectively, in organoid culture. n = 5 per group. h, i, The transitional epithelium is also present at the SCJ of the anus (h) and cervix (i). Lineage tracing with the Krt7CreER mouse line confirmed that KRT7+ cells serve as progenitors for the transitional epithelium. n = 3 per group. Scale bars, 20 μm.

Extended Data Figure 5 Loss of p63 prevents the stratification of KRT7+ columnar epithelium during embryonic development.

a, Proposed REC model of downward expansion of p63+KRT7 basal cells and retreatment of p63KRT7+ embryonic cells. b, The columnar epithelium lining the mouse forestomach and the SCJ expresses p63, KRT7 and KRT8 from E11.5 to E16.5. Note that Claudin18 expression is limited to the hindstomach epithelium. n = 5. c, Expression of KRT7 is restricted to the SCJ transitional epithelium at E18.5, and basal cells (arrowheads) express p63, KRT5, KRT7 and low levels of KRT8, but not CLDN18. n = 5. d, Gradual restriction of KRT7 expression to the SCJ transitional epithelium during development. Initially, the simple columnar epithelium lining the forestomach and SCJ expresses both p63 and KRT7. On stratification, the forestomach epithelium loses KRT7 expression but basal cells at the SCJ maintain expression of both p63 and KRT7. e, Lineage tracing of epithelial progenitor cells (p63 promoter active) in p63CreER/CreER;R26LacZ (p63-null) mutants. f, Whole-mount X-gal staining of the oesophagus and stomach isolated from p63CreER/CreER;R26LacZ mutants and p63CreER/+;R26LacZ controls. n = 3. g, h, The simple columnar epithelium that lines the forestomach (g) and oesophagus (h) of p63-null mutants is derived from basal progenitor cells (p63 promotor active), as indicated by X-gal staining. n = 3 per group. i, Normal oesophagus and forestomach is lined by simple columnar epithelium at E11.5. n = 3. Es, oesophagus; FS, forestomach; HS, hindstomach; Tr, trachea. Scale bars, 20 μm.

Extended Data Figure 6 Ectopic CDX2 expression promotes intestinal metaplasia of the transitional epithelium at the SCJ.

a, Targeted expression of CDX2 in basal progenitor cells of Krt5CreER;otet-CDX2-T2A-mCherry mice. Dox water was given every other week for three months to induce CDX2 and mCherry expression. b, CDX2 overexpression leads to the expansion of the transitional epithelium at the SCJ at the first week of Dox treatment. n = 3 per group. c, Dox treatment for four weeks promotes further expansion of the transitional epithelium at the SCJ and the epithelium presents MLE characteristics, with the co-expression of the columnar markers KRT8 and KRT7 and the squamous marker p63. Note that some basal cells start to lose p63 expression as they gain the expression of the AGR2 intestinal marker. n = 3 per group. d, Intestinal metaplasia is apparent after eight weeks of Dox treatment; some metaplastic cells lose p63 expression. n = 4 per group. Scale bars, 20 μm.

Extended Data Figure 7 Ectopic CDX2 expression promotes intestinal metaplasia of the transitional epithelium.

a, Intestinal metaplasia occurs in Krt5rtTA;otet-CDX2 mutants given Dox water for three months, as shown by PAS staining. n = 5 per group. b, Goblet cells enriched with vesicles (asterisks) are present in the SCJ of Krt5rtTA;otet-CDX2 mutants after three months of Dox treatment, as shown by electron microscope. n = 3 per group. c, KRT7 is expressed by both Barrett’s oesophagus and MLE but not the neighbouring squamous epithelium. Residual CDX2 is expressed in a subpopulation of the metaplastic columnar cells, although KRT5 expression is not detectable. n = 5 per group. d, Reduced expression of basal cell genes (p63 and Krt5) and increased expression of the intestinal genes (Vil1, Agr2, Muc2, Muc4 and Tff3) during intestinalization of the SCJ after CDX2 overexpression. Not significant (ns), P > 0.05; *P < 0.05; **P < 0.001; two-tailed Student’s t-test and n = 3 independent experiments. e, Normal SCJ structure is maintained in control mice (otet-CDX2-T2A-mCherry) following three months of Dox treatment. n = 5. f, CDX2 overexpression does not promote columnar metaplasia in the oesophagus and forestomach. Squamous hyperplasia is present in the forestomach (dotted black line). Note that CDX2 expression does not induce ectopic expression of KRT7 in the stratified squamous epithelium. n = 5. G, goblet; N, nucleus. Scale bars, 20 μm.

Extended Data Figure 8 Intestinal metaplasia is maintained even after withdrawal of Dox in Krt5rtTA;otet-CDX2-T2A-mCherry mutants.

a, Severe metaplasia develops at the SCJ of mutants that have been treated with Dox for the first 13 weeks and chased for another 11 weeks. n = 3 per group. b, The metaplastic cells remain at the SCJ even after withdrawal of Dox water. The metaplastic cells express KRT7 and KRT8. Note that mCherry, which indicates CDX2 expression, is not detected. n = 3 per group. c, Metaplastic cells maintain AGR2 and Villin 1 expression. n = 3 per group. Scale bars, 20 μm.

Extended Data Figure 9 Ectopic CDX2 expression promotes intestinal metaplasia of the transitional epithelium in Krt7CreER;R26rtTA;otet-CDX2-T2A-mCherry mutants.

a, Induction of CDX2 overexpression by combined treatment of tamoxifen and doxycycline. b, Thirty days of CDX2 expression drives the differentiation of the transitional basal cells into intestinal-like epithelium, including goblet cells, in Krt7CreER;R26rtTA;otet-CDX2-T2A-mCherry mice. n = 3 per group. c, Ninety days of CDX2 overexpression leads to prominent intestinal metaplasia of the transitional basal progenitor cells, as indicated by intestinal markers. n = 4 per group. Scale bars, 20 μm.

Extended Data Figure 10 Intestinal metaplasia develops in air–liquid interface culture of the transitional (p63+KRT7+) but not the squamous (p63+KRT7) basal progenitor cells on CDX2 expression.

a, Dox-induced CDX2 expression. b, Intestinal metaplasia occurs in Dox-treated transitional (p63+KRT7+), but not squamous basal (p63+KRT7), progenitor cells. Note that p63+KRT7 basal cells generate a thick keratin layer in the air–liquid interface culture and the differentiated cells express loricrin. n = 5 per group. Scale bars, 20 μm.

Extended Data Figure 11 Different responses to CDX2 overexpression in transitional (p63+ KRT7+) and squamous (p63+ KRT7-) basal progenitor cells in vitro. Human and mouse MLE presents similar gene expression.

a, Two distinct basal progenitor populations (p63+KRT7 and p63+KRT7+) are present at the human SCJ, as indicated by flow cytometric analysis. n = 3 independent experiments. b, Induction of CDX2 overexpression with Dox treatment of CDX2 virus-infected human SCJ basal progenitor cells. c, CDX2 overexpression promotes intestinal metaplasia of p63+KRT7+ cells. The metaplastic columnar cells are PAS+ and express Villin 1, Muc2 and TFF3. n = 6 per group. d, Ectopic CDX2 expression does not promote intestinal metaplasia of the stratified squamous epithelium in organoids formed by p63+KRT7 squamous basal cells. n = 4 per group. e, The transitional epithelium with underlying basal cells is considerably expanded in patients with long-term gastro-oesophageal acid reflux. Dotted lines indicate the basement membrane. n = 3. f, The transitional epithelium with basal cells is amplified in Barrett’s oesophagus mixed with MLE. n = 5. g, Similar phenotypic presentations of human MLE and mouse MLE developed at the SCJ following CDX2 overexpression and oesophageal–duodenal anastomosis surgery. Human MLE, n = 10; Krt5rtTA;otet-CDX2 mutant mice, n = 5; surgical mice, n = 5. h, Goblet cells in human Barrett’s oesophagus are positive for Alcian blue and PAS staining. Barrett’s epithelium loses the expression of KRT5 and p63 but maintains the expression of KRT7. Note that Barrett’s oesophagus gains CDX2, MUC2, AGR2 and Villin 1 expression. n = 12. Scale bars, 20 μm.

Supplementary information

Reporting Summary (PDF 118 kb)

Supplementary Table 1

This file contains Supplementary Table 1 - primer sequences used in Qpcr. (XLSX 10 kb)

Supplementary Table 2

This file contains Supplementary Table 2 - basic information about patients with MLE/BE and normal SCJ. (XLSX 11 kb)

Supplementary Table 3

This file contains Supplementary Table 3 - source Data for qPCR (related to Extended Data Figure 7d). (XLSX 11 kb)

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Jiang, M., Li, H., Zhang, Y. et al. Transitional basal cells at the squamous–columnar junction generate Barrett’s oesophagus. Nature 550, 529–533 (2017). https://doi.org/10.1038/nature24269

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