Wnt5a Pathway Critical in Stem Cell Response to Gastric Injury

Study data published in Gut outline the role of the Wnt5a pathway in the response of the transcription factor Mist1 (Mist1+) gastric isthmus stem cells to injury and inflammation. In mouse models of gastric epithelial injury, genetic deletion of Wnt5a significantly impacted Mist1+ cell proliferation, emphasizing the role of this pathway in gastric repair. 

Chronic gastric injury and inflammation can lead to excess stem cell activation, which in turn is a risk factor for tumor development. Prior research has highlighted stem cells marked by Mist1+ as potential sites of cancer development in the gastric corpus and antrum. Investigators used mouse models to further investigate the regulation of Mist1+ stem cells in the response to gastric injury and inflammation.

Two models of inflammation were examined: acetic acid-induced ulcer and infection with Helicobacter felis (H. felis). Mist1+ lineage tracing was examined at 2 timepoints after injury: early (7-30 days) and late (30-90 days).

Investigators also tested the contribution of corpus Lgr5+ cells to epithelial regeneration. Mice were treated with diphtheria toxin (DT) to ablate Lgr5-DTR+ cells, then underwent the same gastric injury and inflammation induction procedures. Lineage tracing was performed in these mice and controls to test the impact of chief cell deficiency in gastric regeneration. Finally, Wnt5a knockout mice were used to assess the role of Wnt5a in wound repair and lineage tracing from the Mist1+ stem cells.

Both acute injury and inflammation increased lineage tracing from Mist1;TdT+ cells. Within 7 days of ulcer induction, an increased number of traced cells derived from isthmus Mist1;TdT+ stem cells were observed in the “healing zone” compared with the unharmed tissue.

Similarly, lineage tracing from Mist1;TdT+ cells was also increased in H. felis inflammation models. These changes could be observed as early as 30 days after infection with H. felis. Lgr5 ablation did not appear to affect Mist1;TdT+ tracing in gastric wound healing. This observation was consistent across gastric ulcer and H. felis infection models.

In gastric injury models, Wnt5a knockout mice had substantially larger ulcer size at day 10 compared to non-Wnt5a-deficient controls. As such, Wnt5a deficiency appeared to impair gastric ulcer healing. Additionally, by depleting innate lymphoid type 2 cells (ILC-2)—the main innate source of Wnt5a—investigators also observed reduced proliferation of Mist1+ isthmus stem cells. Compared to basal chief cells, the Wnt5a receptor Frizzled5 (Fzd5) was significantly enriched in Mist1+ isthmus stem cells compared with basal chief cells, suggesting greater sensitivity to Wnt5a signaling.

Results from this study outline key signaling pathways in gastric regeneration following injury and inflammation. Per mouse models, Wnt5a plays a key role in the proliferation of Mist1+ isthmus stem cells. “Future studies will have to show if Wnt5a and ILC-2 could be used as predictors for tissue regeneration and healing processes in gastric ulcer patients,” investigators wrote. “The Wnt5a-Fzd5 [signaling] axis plays an important role in gastric regeneration and inflammation and could be a potential target in patients with peptic ulcer disease.”

Reference

Nienhüser H, Kim W, Malagola E, et al. Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice. Gut. 2021;70(4):654-665.