Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance
Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance
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DOI：
10.1172/jci.insight.125068
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发表时间：
2019-03-07
期刊：
影响因子：
8
通讯作者：
Hong, Young-Kwon
中科院分区：
文献类型：
--
作者：
Choi, Dongwon;Park, Eunkyung;Hong, Young-Kwon
淋巴系统在组织稳态、脂质吸收和免疫细胞运输中起着至关重要的作用。虽然淋巴阀保证淋巴液的单向流动，但淋巴液流动本身控制淋巴阀的形成。在这里，我们证明了机械激活的离子通道Piezo1感知振荡剪切应力（OSS），并将信号纳入控制淋巴阀发育和维护的遗传程序中。使用泛内皮Cre驱动因子（Cdh5[PAC]-CreER(T2)）或淋巴特异性Cre驱动因子（Prox1-CreER(T2)）在时间控制下删除Piezo1，同样可以抑制新生小鼠淋巴阀的形成。此外，成人淋巴管中Piezo1的缺失导致了严重的淋巴阀变性。在培养的淋巴内皮细胞（LECs）中，Piezo1敲除在很大程度上消除了oss诱导的淋巴阀特征基因的上调。相反，在没有OSS的情况下，异位Piezo1过表达上调淋巴阀基因。值得注意的是，使用化学激动剂Yoda1激活Piezo1不仅加速了动物淋巴阀的形成，而且在未暴露于OSS的培养LECs中也引发了一些淋巴阀基因的上调。总之，我们的研究共同表明，Piezo1是控制淋巴阀发育和维持的机械转导途径中的力传感器，并且Piezo1激活是先天性和手术相关淋巴水肿的潜在新治疗策略。
The lymphatic system plays crucial roles in tissue homeostasis, lipid absorption, and immune cell trafficking. Although lymphatic valves ensure unidirectional lymph flows, the flow itself controls lymphatic valve formation. Here, we demonstrate that a mechanically activated ion channel Piezo1 senses oscillating shear stress (OSS) and incorporates the signal into the genetic program controlling lymphatic valve development and maintenance. Time-controlled deletion of Piezo1 using a pan-endothelial Cre driver (Cdh5[PAC]-CreER(T2)) or lymphatic-specific Cre driver (Prox1-CreER(T2)) equally inhibited lymphatic valve formation in newborn mice. Furthermore, Piezo1 deletion in adult lymphatics caused substantial lymphatic valve degeneration. Piezo1 knockdown in cultured lymphatic endothelial cells (LECs) largely abrogated the OSS-induced upregulation of the lymphatic valve signature genes. Conversely, ectopic Piezo1 overexpression upregulated the lymphatic valve genes in the absence of OSS. Remarkably, activation of Piezo1 using chemical agonist Yoda1 not only accelerated lymphatic valve formation in animals, but also triggered upregulation of some lymphatic valve genes in cultured LECs without exposure to OSS. In summary, our studies together demonstrate that Piezo1 is the force sensor in the mechanotransduction pathway controlling lymphatic valve development and maintenance, and Piezo1 activation is a potentially novel therapeutic strategy for congenital and surgery-associated lymphedema.