ANKRD22 Drives Rapid Proliferation of Lgr5 + Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury.

Background & Aims: Rapid gastric epithelial progenitor cell (EPC) proliferation and inflammatory response inhibition play key roles in promoting the repair of gastric mucosal damage. However, specific targets inducing these effects are unknown. In this study, we explored the effects of a potential target, Ankyrin repeat domain 22 (ANKRD22).
Methods: An acute gastric mucosal injury model was established with Ankrd22 ^-/- and Ankrd22 ^+/+ mice by intragastric administration of acidified ethanol. Organoid culture and flow cytometry were performed to evaluate the effects of ANKRD22 on leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5 ⁺ ) gastric EPC proliferation. The mechanisms by which ANKRD22 affects gastric EPC proliferation and inflammatory responses were explored by mitochondrial Ca ²⁺ influx and immunoblotting. Candidate ANKRD22 inhibitors then were screened virtually and validated in vitro and in vivo.
Results: After acute gastric mucosal injury, the number of Lgr5 ⁺ gastric EPCs was increased significantly in Ankrd22 ^-/- mice compared with that in Ankrd22 ^+/+ mice. Moreover, Ankrd22 knockout attenuated inflammatory cell infiltration into damaged gastric tissues. ANKRD22 deletion also reduced mitochondrial Ca ²⁺ influx and cytoplasmic nuclear factor of activated T cells in gastric epithelial cells and macrophages, which further induced Lgr5 ⁺ gastric EPC proliferation and decreased macrophage release of tumor necrosis factor-α and interleukin 1α. In addition, a small molecule, AV023, was found to show similar effects to those produced by ANKRD22 deletion in vitro. Intraperitoneal injection of AV023 into the mouse model promoted the repair of gastric mucosal damage, with increased proliferation of Lgr5 ⁺ gastric EPCs and visible relief of inflammation.
Conclusions: ANKRD22 inhibition is a potential target-based therapeutic approach for promoting the repair of gastric mucosal damage.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)