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Lgr5

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach(1), but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5(+) intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway(2). However, the contribution of pyloric LGR5(+) stem cells to gastric cancer following dysregulation of the WNT pathway-a frequent event in gastric cancer in humans(3)-is unknown. Here we use comparative profiling of LGR5(+) stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5(+) compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5(+) cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.AQP5 is identified as a marker for pyloric stem cells in humans and mice, and stem cells in the AQP5(+) compartment are shown to be a source of invasive gastric cancer in mouse models.

Bronchoconstriction is a key feature of asthma but the disease drivers and signalling mechanisms involved are not fully understood. TRPM3, a member of the Transient Receptor family of ion channels, has recently been shown to activate airway sensory nerves in both animal and human tissue (Bonvini et al 2018, AJRCCM:197:A7411). However, its role in direct bronchoconstriction is currently untested. We therefore aimed to investigate the role of TRPM3 in contraction of airway smooth muscle. The TRPM3 agonist CIM0216 was shown to cause bronchospasm in vivo in the anaesthetised guinea pig (GP), independent of sensory nerve activation. Tissue bath assays indicated that CIM0216 caused a concentration dependent contraction of GP trachea, which was inhibited by the TRPM3 antagonist Primidone. Further investigation revealed that both removal of the epithelium and addition of the selective NK2 antagonist MEN10376 significantly inhibited the contraction induced by CIM0216. RTPCR studies revealed that the TRPM3 gene was expressed on GP epithelial cells, and the TACR2 gene, which is the receptor for NK2, was expressed on GP ASM. These data suggest that activation of TRPM3 on epithelial cells leads to the release of tachykinins which activate the NK2 receptor on airway smooth muscle to cause bronchoconstriction. Tachykinins such as NKA have been well documented to cause contraction in the asthmatic airway. Although further work is required, this implicates the TRPM3 receptor on epithelial cells as a potential non-neuronal source of tachykinin release and subsequent bronchoconstriction, and also highlights it as a possible novel therapeutic target.