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Polarised Epithelial Monolayers of the Gastric Mucosa Reveal Insights

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Polarised Epithelial Monolayers of the Gastric Mucosa Reveal Insights Gut Online First, published on February 21, 2018 as 10.1136/gutjnl-2017-314540 Helicobacter pylori ORIGINAL ARTICLE Polarised epithelial monolayers of the gastric mucosa Gut: first published as 10.1136/gutjnl-2017-314540 on 21 February 2018. Downloaded from reveal insights into mucosal homeostasis and defence against infection Francesco Boccellato,1 Sarah Woelffling,1 Aki Imai-Matsushima,1 Gabriela Sanchez,1 Christian Goosmann,1 Monika Schmid,1 Hilmar Berger,1 Pau Morey,1 Christian Denecke,2 Juergen Ordemann,3 Thomas F Meyer1 ► Additional material is ABSTRact published online only. To view Objective Helicobacter pylori causes life-long Significance of this study please visit the journal online colonisation of the gastric mucosa, leading to chronic (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2017- 314540). inflammation with increased risk of gastric cancer. The gastric mucosa consists of a columnar 1 Research on the pathogenesis of this infection would ► Department of Molecular epithelial monolayer protected by mucus. Biology, Max Planck Institute strongly benefit from an authentic human in vitro model. for Infection Biology, Berlin, Design Antrum-derived gastric glands from surgery This defence barrier can be colonised by Germany specimens served to establish polarised epithelial Helicobacter pylori, triggering inflammation 2Center for Bariatric and monolayers via a transient air–liquid interface culture with an increased risk of gastric cancer. Metabolic Surgery, Charité stage to study cross-talk with H. pylori and the adjacent ► Recent years have seen the development of University Medicine, Berlin, human gastric organoid cultures enabling Germany stroma. 3Department of Bariatric and Results The resulting ’mucosoid cultures’, so named mechanistic investigations in primary cells. Metabolic Surgery, Helios because they recapitulate key characteristics of the ► Yet, with regard to the assessment of infection Clinics, Berlin, Germany gastric mucosa, represent normal stem cell-driven processes, plain organoids present suboptimal cultures that can be passaged for months. These highly conditions for infection studies, due to their Correspondence to polarised columnar epithelial layers encompass the closed spherical shape, luminal polarisation Professor Thomas F Meyer, with accumulating deposition of apoptotic cells Department of Molecular various gastric antral cell types and secrete mucus at the Biology, Max Planck Institute for apical surface. By default, they differentiate towards a in the lumen, as well as their encapsulation into Infection Biology, Berlin 10117, foveolar, MUC5AC-producing phenotype, whereas Wnt extracellular matrix. Germany; meyer@ mpiib- berlin. signalling stimulates proliferation of MUC6-producing http://gut.bmj.com/ mpg. de What are the new findings? cells and preserves stemness—reminiscent of the gland We have regenerated the columnar epithelium base. Stromal cells from the lamina propria secrete Wnt ► Received 24 May 2017 of the human gastric mucosa following the Revised 30 January 2018 inhibitors, antagonising stem-cell niche signalling and approach of an air–liquid interface (ALI) Accepted 31 January 2018 inducing differentiation. On infection with H. pylori, a culture. However, in contrast to standard strong inflammatory response is induced preferentially ALI cultures, the gastric polarised epithelial in the undifferentiated basal cell phenotype. Infection monolayers (mucosoid cultures) are long-lived. of cultures for several weeks produces foci of viable on October 3, 2021 by guest. Protected copyright. Mucosoid cultures constitute stable cultures bacteria and a persistent inflammatory condition, while consisting of highly polarised cells comprised the secreted mucus establishes a barrier that only few of all the gastric gland lineages. They allow for bacteria manage to overcome. homeostatic infections, eg, with H. pylori, for Conclusion Gastric mucosoid cultures faithfully periods of several weeks. reproduce the features of normal human gastric Under the influence of Wnt signalling, gastric epithelium, enabling new approaches for investigating ► mucosoid cultures differentiate into phenotypes the interaction of H. pylori with the epithelial surface and typical of the base of the gland. Stromal cells the cross-talk with the basolateral stromal compartment. secrete Wnt inhibitors and drive differentiation Our observations provide striking insights in the towards a foveolar phenotype. Only basal cells regulatory circuits of inflammation and defence. respond to H. pylori infection with a strong inflammatory response. ► Gastric mucosoid cultures produce and INTRODUCTION accumulate abundant mucus on the apical side, Helicobacter pylori, a Gram-negative bacterium which prevents immediate pathogen contact that infects around half of the human population, with epithelial cells and controls bacterial To cite: Boccellato F, can persist in the stomach over decades and in some proliferation. Woelffling S, Imai- cases lead to gastric adenocarcinoma.1–4 The excep- Matsushima A, et al. Gut Epub ahead of print: [please tional ability to escape the mucosal immune defence include Day Month Year]. appears intrinsically connected with a chronic infection and tissue repair through enhanced doi:10.1136/ inflammatory status.5–7 The inflammatory response regeneration, an aspect that has been implicated in gutjnl-2017-314540 of the mucosa mediates the host defence against tumour development.8 Boccellato F, et al. Gut 2018;0:1–14. doi:10.1136/gutjnl-2017-314540 1 Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Helicobacter pylori features represent key advantages over existing culture methods Significance of this study and permit advanced studies on the mechanisms of chronic inflammation, the role of mucus in epithelial defence and the Gut: first published as 10.1136/gutjnl-2017-314540 on 21 February 2018. Downloaded from How might it impact on clinical practice in the foreseeable factors that control epithelial homeostasis during infection. As future? such, it represents an important new tool for illuminating the ► The gastric mucosoid culture model will generate new mechanisms underlying gastric carcinogenesis. insights into the effects of long-term infection with H. pylori on epithelial cells, paving the way for new therapeutic RESULTS approaches against infection and its sequelae. Establishment of gastric mucosoid cultures on filters ► The gastric mucosoid culture model is likely to be Gastric glands were isolated from human antrum sleeve gastrec- transferrable to other columnar epithelia. It promises to be 14 a versatile drug-screening tool, enabling compound testing tomy samples (figure 1A) as previously described. Antrum with differential applications on either or both the apical (figure 1A dotted line) was identified as the region opposite to and the basal sides. It also allows assessment of molecular the fundus (marked by the surgeon) that does not contain rugae communication in co-culture with other cell types, such as typical of the corpus. Dissociated cells from fresh tissue or gastric myofibroblasts and immune cells. organoids were seeded onto collagen-coated polycarbonate filters. After 3 days, the medium on top of the cells is removed ► The robust mucus production will enable insights into the protective role of this important mucosal component and to initiate air–liquid interface conditions (figure 1B). Over the provide new options for future therapeutic drug targeting. next 10 days, they develop a mature epithelial morphology, becoming progressively taller (figure 1C). After 10–13 days, transparent mucus starts to accumulate on top of the monolayer 9 (~50–100 µL/week) and has to be removed regularly (see online H. pylori adheres to the gastric foveolae, but it can eventually supplementary movie). Cells from mature monolayers can infiltrate the glands10 and interact with the stem cell compart- be passaged onto new filters or grown as organoids and vice ment located at the base.11 Experiments in mice have revealed versa, thus the two methods are interconvertible. Gastric muco- that hyperplasia and other pathological changes in the stomach soid cultures contain sporadic Ki67-positive proliferative cells occur mainly in response to such deep glandular colonisation.11 (figure 1D), even after 1 and 2 months of culture (figure 1E,F), More detailed investigations into the infection dynamics there- indicating that they are stable even without passaging. fore would benefit from a robust in vitro model that recapitu- We used quantitative reverse transcription PCR (qRT-PCR) to lates the features of the basal glandular compartment. monitor the long-term stability of cultures that were passaged In recent years, an increased understanding of stem cell once a month. Expression of the gastric epithelial markers biology has driven the development of organoid cultures as a KRT8, 18 and 19, EPCAM and CHD1 remained constant for way of maintaining adult stem cells in vitro,12 13 including those up to 7 months (figure 1G). Expression of the gastric stem cell obtained by isolating glands from gastric tissue samples.14 15 marker Lgr512 also remained constant after the first passage, The epithelium of the antrum is maintained by Lgr5+stem cells 16 as did β-catenin and CD44, a marker of proliferating and stem located at the base of the glands where MUC6 is secreted. cells in the stomach24 (figure 1H). At the same time, markers of
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