Moneme Chioma, Olutoye Oluyinka O, Sobstel Michał F, Zhang Yuwen, Zhou Xinyu, Kaminer Jacob L, Hsu Britney A, Shen Chengli, Mandal Arabinda, Li Hui, Yu Ling, Balaji Swathi, Keswani Sundeep G, Cheng Lily S
Department of Surgery, University of Virginia, Charlottesville, VA, United States.
Department of Surgery, Baylor College of Medicine, Houston, TX, United States.
Front Mol Neurosci. 2024 Dec 20;17:1474025. doi: 10.3389/fnmol.2024.1474025. eCollection 2024.
Dysfunction of the enteric nervous system (ENS) is linked to a myriad of gastrointestinal (GI) disorders. Piezo1 is a mechanosensitive ion channel found throughout the GI tract, but its role in the ENS is largely unknown. We hypothesize that Piezo1 plays an important role in the growth and development of the ENS.
Enteric neural crest-derived progenitor cells (ENPC) were isolated from adult mouse intestine and propagated in culture as neurospheres. ENPC-derived neurons were then subject to stretch in the presence or absence of Piezo1 antagonist (GsMTx4). Transcriptomes of stretched and unstretched ENPC-derived cells were compared using bulk RNA sequencing. Enteric neurons were also cultured under static conditions in the presence of Piezo1 agonist (Yoda1) or antagonist. Neuronal phenotype, migration, and recovery from injury were compared between groups.
Though stretch did not cause upregulation of Piezo1 expression in enteric neurons, both stretch and Piezo1 activation produced similar alterations in neuronal morphology. Compared to control, neurite length was significantly shorter when stretched and in the presence of Piezo1 activation. Piezo1 inhibition prevented a significant reduction in neurite length in stretched neurons. Piezo1 inhibition also led to significantly increased neuronal migration, whereas Piezo1 activation resulted in significantly decreased neuronal migration and slower neuronal recovery from injury.
Mechanotransduction plays an important role in regulating normal GI function. Our results suggest that the Piezo1 mechanoreceptor may play an important role in the ENS as its activation leads to decreased neuronal growth and migration. Piezo1 could be an important target for diseases of ENS dysfunction and development.
肠神经系统（ENS）功能障碍与多种胃肠道（GI）疾病相关。Piezo1是一种在整个胃肠道中发现的机械敏感离子通道，但其在肠神经系统中的作用尚不清楚。我们假设Piezo1在肠神经系统的生长和发育中起重要作用。
从成年小鼠肠道中分离出肠神经嵴衍生的祖细胞（ENPC），并在培养中作为神经球进行增殖。然后，在存在或不存在Piezo1拮抗剂（GsMTx4）的情况下，对ENPC衍生的神经元进行拉伸。使用批量RNA测序比较拉伸和未拉伸的ENPC衍生细胞的转录组。肠神经元也在存在Piezo1激动剂（Yoda1）或拮抗剂的静态条件下培养。比较各组之间的神经元表型、迁移和损伤恢复情况。
虽然拉伸并未导致肠神经元中Piezo1表达上调，但拉伸和Piezo1激活均在神经元形态上产生了类似的改变。与对照组相比，在拉伸和Piezo1激活的情况下，神经突长度明显较短。Piezo1抑制可防止拉伸神经元的神经突长度显著缩短。Piezo1抑制还导致神经元迁移显著增加，而Piezo1激活则导致神经元迁移显著减少且神经元损伤恢复较慢。
机械转导在调节正常胃肠道功能中起重要作用。我们的结果表明，Piezo1机械感受器可能在肠神经系统中起重要作用，因为其激活会导致神经元生长和迁移减少。Piezo1可能是肠神经系统功能障碍和发育疾病的重要靶点。
