LGR5+ Stem cells in epithelial homeostasis, regeneration and disease of the stomach
Profefssor Nicholas Barker, Research Director, Epithelial Stem Cell Group, Institute of Medical Biology Singapore; Visiting Professor, CRM, University of Edinburgh; and Research Professor, Kanazawa University, Japan
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The gastric epithelium continuously self-renews throughout life, driven by limited reservoirs of resident Lgr5+ adult stem cells. In vivo ablation of Lgr5+ cells severely impairs epithelial homeostasis in both the pyloric antrum and the corpus. Transcriptome analysis of the pyloric Lgr5+ stem cells reveals novel gastric stem cell-specific markers that can be used to selectively target cancer-causing mutations to the Lgr5+ stem cell compartment in the stomach as a means of evaluating their contribution to gastric cancer initiation. These new pyloric stem cell markers include membrane-expressed genes that can be used to isolate human gastric stem cells for therapeutic applications. We additionally document Lgr5 expression on a subset of Chief cells in the corpus. In vivo lineage tracing using a novel Lgr5-2A-CreERT2 model and ex vivo organoid culture assays reveals these to be a damage-inducible stem cell population contributing to epithelial repair following Parietal cell atrophy. Conditional mutation of these damage-inducible Lgr5+ corpus stem cells drives gastric cancer initiation in vivo, identifying these cells as a source of gastric cancer. We also present a new mouse model of human metastatic gastric cancer, incorporating the first stomach-specific Cre line, Cldn-18-CreERT2. Finally, we report the identification of novel homeostatic and/or injury-driven Lgr5+ stem cells in tissues such as the liver, eosophagus, muscle and lung.