Somatic stem cells constantly adjust their self-renewal and lineage commitment by integrating various environmental cues to maintain tissue homeostasis. Although numerous chemical and biological signals have been identified that regulate stem-cell behaviour, whether stem cells can directly sense mechanical signals in vivo remains unclear. Here we show that mechanical stress regulates stem-cell differentiation in the adult Drosophila midgut through the stretch-activated ion channel Piezo. We find that Piezo is specifically expressed in previously unidentified enteroendocrine precursor cells, which have reduced proliferation ability and are destined to become enteroendocrine cells. Loss of Piezo activity reduces the generation of enteroendocrine cells in the adult midgut. In addition, ectopic expression of Piezo in all stem cells triggers both cell proliferation and enteroendocrine cell differentiation. Both the Piezo mutant and overexpression phenotypes can be rescued by manipulation of cytosolic Ca2+ levels, and increases in cytosolic Ca2+ resemble the Piezo overexpression phenotype, suggesting that Piezo functions through Ca2+ signalling. Further studies suggest that Ca2+ signalling promotes stem-cell proliferation and differentiation through separate pathways. Finally, Piezo is required for both mechanical activation of stem cells in a gut expansion assay and the increase of cytosolic Ca2+ in response to direct mechanical stimulus in a gut compression assay. Thus, our study demonstrates the existence of a specific group of stem cells in the fly midgut that can directly sense mechanical signals through Piezo.

中文翻译：

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拉伸激活的压电通道对干细胞分化的机械调节

体干细胞通过整合各种环境线索来不断调整其自我更新和谱系承诺，以维持组织稳态。尽管已经确定了许多调节干细胞行为的化学和生物信号，但干细胞是否可以在体内直接感知机械信号仍不清楚。在这里，我们显示机械应力通过拉伸激活的离子通道 Piezo 调节成年果蝇中肠的干细胞分化。我们发现 Piezo 在以前未鉴定的肠内分泌前体细胞中特异性表达，这些前体细胞的增殖能力降低，注定会成为肠内分泌细胞。压电活性的丧失会减少成人中肠中肠内分泌细胞的生成。此外，Piezo 在所有干细胞中的异位表达触发细胞增殖和肠内分泌细胞分化。Piezo 突变体和过表达表型都可以通过操纵细胞溶质 Ca2+ 水平来挽救，并且细胞溶质 Ca2+ 的增加类似于 Piezo 过表达表型，这表明 Piezo 通过 Ca2+ 信号传导发挥作用。进一步的研究表明，Ca2+ 信号通过不同的途径促进干细胞增殖和分化。最后，Piezo 是肠道扩张试验中干细胞的机械激活和肠道压缩试验中响应直接机械刺激而增加细胞溶质 Ca2+ 所必需的。因此，我们的研究表明果蝇中肠中存在一组特定的干细胞，它们可以通过压电直接感知机械信号。