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Original research
Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach
  1. Kevin A Bockerstett1,
  2. Scott A Lewis2,
  3. Kyle J Wolf1,
  4. Christine N Noto1,
  5. Nicholas M Jackson1,
  6. Eric L Ford1,
  7. Tae-Hyuk Ahn2,
  8. Richard J DiPaolo1
  1. 1 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
  2. 2 Department of Computer Science, Saint Louis University, Saint Louis, Missouri, USA
  1. Correspondence to Dr Richard J DiPaolo, Molecular Microbiology & Immunology, St. Louis University, Saint Louis, MO 63104, USA; richard.dipaolo{at}health.slu.edu

Abstract

Objective Spasmolytic polypeptide-expressing metaplasia (SPEM) is a regenerative lesion in the gastric mucosa and is a potential precursor to intestinal metaplasia/gastric adenocarcinoma in a chronic inflammatory setting. The goal of these studies was to define the transcriptional changes associated with SPEM at the individual cell level in response to acute drug injury and chronic inflammatory damage in the gastric mucosa.

Design Epithelial cells were isolated from the gastric corpus of healthy stomachs and stomachs with drug-induced and inflammation-induced SPEM lesions. Single cell RNA sequencing (scRNA-seq) was performed on tissue samples from each of these settings. The transcriptomes of individual epithelial cells from healthy, acutely damaged and chronically inflamed stomachs were analysed and compared.

Results scRNA-seq revealed a population Mucin 6 (Muc6)+gastric intrinsic factor (Gif)+ cells in healthy tissue, but these cells did not express transcripts associated with SPEM. Furthermore, analyses of SPEM cells from drug injured and chronically inflamed corpus yielded two major findings: (1) SPEM and neck cell hyperplasia/hypertrophy are nearly identical in the expression of SPEM-associated transcripts and (2) SPEM programmes induced by drug-mediated parietal cell ablation and chronic inflammation are nearly identical, although the induction of transcripts involved in immunomodulation was unique to SPEM cells in the chronic inflammatory setting.

Conclusions These data necessitate an expansion of the definition of SPEM to include Tff2+Muc6+ cells that do not express mature chief cell transcripts such as Gif. Our data demonstrate that SPEM arises by a highly conserved cellular programme independent of aetiology and develops immunoregulatory capabilities in a setting of chronic inflammation.

  • GASTRIC METAPLASIA
  • GASTRIC CANCER
  • GASTRITIS
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Footnotes

  • KAB and SAL contributed equally.

  • Contributors KAB was responsible for study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript and revision of manuscript. SAL was responsible for analysis and interpretation of scRNA-seq data sets, drafting of the manuscripts and revision of the manuscript. KJW was responsible for interpretation of data and revision of the manuscript. CNN and NMJ assisted in data acquisition, interpretation and revision of the manuscript. ELF acquired data and provided technical support. T-HA was involved in study concept and design, analysis and interpretation of data and revision of the final manuscript. RJD obtained funding and was involved in study concept and design, data interpretation and revision of the manuscript.

  • Funding KAB was supported by a National Institutes of Health (NIH)/NIDDK NRSA Predoctoral fellowship (F30 DK118873). RJD was supported by the NIH National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK110406). RJD was previously supported by the American Cancer Society (RSG-12-171-01-LIB) and the American Gastroenterological Association Funderburg Award.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

  • Author note Transcript profiling: database link will be provided on acceptance.

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