Mist1+ Gastric Isthmus Stem Cells Are Regulated by Wnt5a and Expand in Response to Injury and Inflammation in Mice

Overview

Journal Gut

Specialty Gastroenterology

Date 2020 Jul 26

PMID 32709613

Citations 25

Authors

Henrik Nienhuser

Woosook Kim

Ermanno Malagola

Tuo Ruan

Giovanni Valenti

Moritz Middelhoff

Adam Bass

Channing J Der

Yoku Hayakawa

Timothy C Wang

Affiliations

Soon will be listed here.

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 . 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.

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References

Leushacke M, Tan S, Wong A, Swathi Y, Hajamohideen A, Tan L . Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol. 2017; 19(7):774-786. DOI: 10.1038/ncb3541. View

Shao Y, Zheng Q, Wang W, Xin N, Song X, Zhao C . Biological functions of macrophage-derived Wnt5a, and its roles in human diseases. Oncotarget. 2016; 7(41):67674-67684. PMC: 5341904. DOI: 10.18632/oncotarget.11874. View

Choi E, Lantz T, Vlacich G, Keeley T, Samuelson L, Coffey R . Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut. 2017; 67(9):1595-1605. PMC: 5815959. DOI: 10.1136/gutjnl-2017-313874. View

Tarnawski A, Stachura J, Krause W, Douglass T, Gergely H . Quality of gastric ulcer healing: a new, emerging concept. J Clin Gastroenterol. 1991; 13 Suppl 1:S42-7. DOI: 10.1097/00004836-199112001-00007. View

Karam S, Leblond C . Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell. Anat Rec. 1993; 236(2):259-79. DOI: 10.1002/ar.1092360202. View

Buttler K, Becker J, Pukrop T, Wilting J . Maldevelopment of dermal lymphatics in Wnt5a-knockout-mice. Dev Biol. 2013; 381(2):365-76. DOI: 10.1016/j.ydbio.2013.06.028. View

Nam K, Lee H, Sousa J, Weis V, ONeal R, Finke P . Mature chief cells are cryptic progenitors for metaplasia in the stomach. Gastroenterology. 2010; 139(6):2028-2037.e9. PMC: 2997152. DOI: 10.1053/j.gastro.2010.09.005. View

Steinhart Z, Pavlovic Z, Chandrashekhar M, Hart T, Wang X, Zhang X . Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nat Med. 2016; 23(1):60-68. DOI: 10.1038/nm.4219. View

Mah A, Yan K, Kuo C . Wnt pathway regulation of intestinal stem cells. J Physiol. 2016; 594(17):4837-47. PMC: 5009769. DOI: 10.1113/JP271754. View

10.

Sessa R, Yuen D, Wan S, Rosner M, Padmanaban P, Ge S . Monocyte-derived Wnt5a regulates inflammatory lymphangiogenesis. Cell Res. 2015; 26(2):262-5. PMC: 4746601. DOI: 10.1038/cr.2015.105. View

11.

Andersson-Rolf A, Zilbauer M, Koo B, Clevers H . Stem Cells in Repair of Gastrointestinal Epithelia. Physiology (Bethesda). 2017; 32(4):278-289. PMC: 5545610. DOI: 10.1152/physiol.00005.2017. View

12.

Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T . The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood. 2006; 108(3):965-73. DOI: 10.1182/blood-2005-12-5046. View

13.

Dickinson S, Sutton C, Brady K, Salerno A, Katopodi T, Williams R . The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation. Stem Cells. 2017; 35(11):2280-2291. PMC: 5707440. DOI: 10.1002/stem.2691. View

14.

Prasad C, Manchanda M, Mohapatra P, Andersson T . WNT5A as a therapeutic target in breast cancer. Cancer Metastasis Rev. 2018; 37(4):767-778. PMC: 6510844. DOI: 10.1007/s10555-018-9760-y. View

15.

Matsuo J, Kimura S, Yamamura A, Koh C, Hossain M, Heng D . Identification of Stem Cells in the Epithelium of the Stomach Corpus and Antrum of Mice. Gastroenterology. 2016; 152(1):218-231.e14. DOI: 10.1053/j.gastro.2016.09.018. View

16.

Burclaff J, Willet S, Saenz J, Mills J . Proliferation and Differentiation of Gastric Mucous Neck and Chief Cells During Homeostasis and Injury-induced Metaplasia. Gastroenterology. 2019; 158(3):598-609.e5. PMC: 7010566. DOI: 10.1053/j.gastro.2019.09.037. View

17.

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M . Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345(11):784-9. DOI: 10.1056/NEJMoa001999. View

18.

Hayakawa Y, Jin G, Wang H, Chen X, Westphalen C, Asfaha S . CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. Gut. 2014; 64(4):544-53. PMC: 4627594. DOI: 10.1136/gutjnl-2014-307190. View

19.

Nam K, ONeal R, Coffey R, Finke P, Barker N, Goldenring J . Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells. Gut. 2011; 61(12):1678-85. PMC: 3767919. DOI: 10.1136/gutjnl-2011-301193. View

20.

Castellanos J, Longman R . The balance of power: innate lymphoid cells in tissue inflammation and repair. J Clin Invest. 2019; 129(7):2640-2650. PMC: 6597213. DOI: 10.1172/JCI124617. View