Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Gastroenterology. 2022 Feb;162(2):535-547.e13. doi: 10.1053/j.gastro.2021.10.026. Epub 2021 Oct 22.
The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like the skin and oral cavity, the GI tract must sense the chemical and physical properties of the its external interface to optimize its function. Specialized sensory enteroendocrine cells (EECs) in GI epithelium interact intimately with luminal contents. A subpopulation of EECs express the mechanically gated ion channel Piezo2 and are developmentally and functionally like the skin's touch sensor- the Merkel cell. We hypothesized that Piezo2+ EECs endow the gut with intrinsic tactile sensitivity.
We generated transgenic mouse models with optogenetic activators in EECs and Piezo2 conditional knockouts. We used a range of reference standard and novel techniques from single cells to living animals, including single-cell RNA sequencing and opto-electrophysiology, opto-organ baths with luminal shear forces, and in vivo studies that assayed GI transit while manipulating the physical properties of luminal contents.
Piezo2+ EECs have transcriptomic features of synaptically connected, mechanosensory epithelial cells. EEC activation by optogenetics and forces led to Piezo2-dependent alterations in colonic propagating contractions driven by intrinsic circuitry, with Piezo2+ EECs detecting the small luminal forces and physical properties of the luminal contents to regulate transit times in the small and large bowel.
The GI tract has intrinsic tactile sensitivity that depends on Piezo2+ EECs and allows it to detect luminal forces and physical properties of luminal contents to modulate physiology.
胃肠道（GI）从摄入的食物中提取营养物质，同时保护机体免受食物中经常存在的感染因子的侵害。因此，大多数动物在 GI 中进行整个消化过程，同时将腔内容物完全保持在体外，由紧密密封的 GI 上皮隔开。因此，与皮肤和口腔一样，GI 必须感知其外部界面的化学和物理特性，以优化其功能。GI 上皮中的专门感觉肠内分泌细胞（EEC）与腔内容物密切相互作用。EEC 亚群表达机械门控离子通道 Piezo2，在发育和功能上与皮肤的触觉传感器-默克尔细胞相似。我们假设 Piezo2+EEC 赋予肠道固有触觉敏感性。
我们生成了 EEC 中具有光遗传学激活剂和 Piezo2 条件性敲除的转基因小鼠模型。我们使用了一系列从单细胞到活体动物的参考标准和新方法，包括单细胞 RNA 测序和光电器生理学、带有腔剪切力的光控器官浴槽，以及在操纵腔内容物物理特性的同时评估 GI 转运的体内研究。
Piezo2+EEC 具有突触连接、机械敏感上皮细胞的转录组特征。光遗传学和力对 EEC 的激活导致由内在电路驱动的结肠传播收缩的 Piezo2 依赖性改变，其中 Piezo2+EEC 检测到腔内容物的小腔力和物理特性，以调节小肠和大肠的转运时间。
GI 具有依赖于 Piezo2+EEC 的固有触觉敏感性，使其能够检测腔内容物的腔力和物理特性，以调节生理学。
