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Original research
Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice
  1. Henrik Nienhüser1,
  2. Woosook Kim1,
  3. Ermanno Malagola1,
  4. Tuo Ruan1,2,
  5. Giovanni Valenti1,
  6. Moritz Middelhoff3,
  7. Adam Bass4,
  8. Channing J Der5,
  9. Yoku Hayakawa6,
  10. Timothy C Wang1
  1. 1 Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
  2. 2 Department of Gastrointestinal Surgery, Huazhong University of Science and Technology, Wuhan, Hubei, China
  3. 3 Klinik und Poliklinik fur Innere Medizin II Gastroenterologie, Klinikum rechts der Isar der Technischen Universitat Munchen, Munchen, Bayern, Germany
  4. 4 Division of Molecular and Cellular Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
  5. 5 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  6. 6 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  1. Correspondence to Dr Timothy C Wang, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA; tcw21{at}columbia.edu

Abstract

Background and aims The gastric epithelium undergoes continuous turnover. Corpus epithelial stem cells located in the gastric isthmus serve as a source of tissue self-renewal. We recently identified the transcription factor Mist1 as a marker for this corpus stem cell population that can give rise to cancer. The aim here was to investigate the regulation of the Mist1+ stem cells in the response to gastric injury and inflammation.

Methods We used Mist1CreERT;R26-Tdtomato mice in two models of injury and inflammation: the acetic acid-induced ulcer and infection with Helicobacter felis. We analysed lineage tracing at both early (7 to 30 days) and late (30 to 90 days) time points. Mist1CreERT;R26-Tdtomato;Lgr5DTR-eGFP mice were used to ablate the corpus basal Lgr5+ cell population. Constitutional and conditional Wnt5a knockout mice were used to investigate the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells.

Results In both models of gastric injury, Mist1+ isthmus stem cells more rapidly proliferate and trace entire gastric glands compared with the normal state. In regenerating tissue, the number of traced gastric chief cells was significantly reduced, and ablation of Lgr5+ chief cells did not affect Mist1-derived lineage tracing and tissue regeneration. Genetic deletion of Wnt5a impaired proliferation in the gastric isthmus and lineage tracing from Mist1+ stem cells. Similarly, depletion of innate lymphoid cells, the main source of Wnt5a, also resulted in reduced proliferation and Mist1+ isthmus cell tracing.

Conclusion Gastric Mist1+ isthmus cells are the main supplier of regenerated glands and are activated in part through Wnt5a pathway.

  • gastric and duodenal ulcers
  • intestinal stem cell
  • helicobacter felis

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Footnotes

  • Contributors Henrik Nienhüser and Timothy C Wang contributed to the study supervision and coordination and the design of the experiments. Henrik Nienhüser, Woosook Kim and Ermanno Malagola conducted and performed all experiments. Moritz Middelhoff and Yoku Hayakawa assisted with various portions of the experiments and data analysis. Henrik Nienhüser, Woosook Kim, Ermanno Malagola, Moritz Middelhoff, Yoku Hayakawa and Timothy C Wang wrote the manuscript.

  • Funding This research was supported by NIH grants (R35CA210088, 5R37DK052778 and 5UO1DK103155) to Timothy C Wang, by a grant of the Deutsche Forschungsgemeinschaft (NI1810/1-1) to Henrik Nienhüser and by a grant of the Deutsche Krebshilfe (70111870) to Moritz Middelhoff. These studies used the resources of the Cancer Center Flow Core Facility funded in part through Center Grant P30CA013696.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available upon reasonable request.

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