ANKRD22 Drives Rapid Proliferation of Lgr5+ Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury
| Autor: | Rui Wang, Dandan Zhong, Yiqing Qiu, Jingni Wu, Yongliang Zhu, Zhenya Song, Jingwen Liu, Hongping Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular ANKRD22 ankyrin repeat domain-containing protein 22 RC799-869 BrdU+ bromodeoxyuridine-incorporating Receptors G-Protein-Coupled Mice FACS fluorescence-activated cell sorting Macrophage IFN-γ interferon-γ Receptor Wnt Signaling Pathway TNF-α tumor necrosis factor α Original Research Mice Knockout medicine.diagnostic_test Chemistry Wnt Wingless/Int1 Gastroenterology LGR5 ELISA enzyme-linked immunosorbent assay Diseases of the digestive system. Gastroenterology FCM flow cytometry Immunohistochemistry mRNA messenger RNA Ssea stage-specific embryonic antigen Mitochondria Sox SRY-box transcription factor NFAT nuclear factor of activated T cells Rhod-2 Dihydrorhod-2 c-Myc Myc proto-oncogene protein AXIN2 axis inhibition protein 2 LPS lipopolysaccharide Tumor necrosis factor alpha FITC fluorescein isothiocyanate RIPA radioimmunoprecipitation assay medicine.symptom IL1α interleukin-1α IHC immunohistochemistry Targeted Gene Repair Gastric Mucosal Injury PBS phosphate-buffered saline Stomach Diseases Inhibitory Compound Inflammation THP-1 Human myeloid leukemia mononuclear cell Immunophenotyping Flow cytometry Structure-Activity Relationship FBS fetal bovine serum Drug Development In vivo Cell Line Tumor medicine Animals Progenitor cell Cell Proliferation Cd cluster of differentiation Hepatology Macrophages Lgr5+ leucine-rich repeat-containing G-protein–coupled receptor 5–positive Membrane Proteins PE Phycoerythrin Macrophage Activation WT wild-type qRT-PCR quantitative reverse-transcription polymerase chain reaction ANKRD22 TBS Tris-buffered saline Disease Models Animal Gene Expression Regulation Mist Muscle intestine and stomach expression Gastric Mucosa CaMKII calmodulin-dependent protein kinase II Cancer research EPC epithelial progenitor cell DMEM Dulbecco’s modified Eagle medium Epithelial Progenitor Cells Biomarkers |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 4, Pp 1433-1455 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| Popis: | 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 Ca2+ 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 Ca2+ 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. Graphical abstract |
| Databáze: | OpenAIRE |
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