Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
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DOI：
10.1161/circresaha.121.320565
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发表时间：
2022-07-08
影响因子：
20.1
通讯作者：
Hong, Young-Kwon
中科院分区：
文献类型：
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作者：
Choi, Dongwon;Park, Eunkyung;Yu, Roy P.;Cooper, Michael N.;Cho, Il-Taeg;Choi, Joshua;Yu, James;Zhao, Luping;Yum, Ji-Eun Irene;Yu, Jin Suh;Nakashima, Brandon;Lee, Sunju;Seong, Young Jin;Jiao, Wan;Koh, Chester J.;Baluk, Peter;McDonald, Donald M.;Saraswathy, Sindhu;Lee, Jong Y.;Jeon, Noo Li;Zhang, Zhenqian;Huang, Alex S.;Zhou, Bin;Wong, Alex K.;Hong, Young-Kwon
PIEZO1突变导致人类淋巴畸形。我们之前已经发现了orai1介导的机械转导途径，该途径通过Notch下调来响应流体流动，从而触发淋巴发芽。然而，其上游机械传感器的身份仍然未知。本研究旨在鉴定和表征将流动介导的外部信号转化为orai1调节的淋巴扩张的分子传感器。采用多种突变小鼠模型、细胞、生化和分子生物学工具以及小鼠尾部淋巴水肿模型来阐明Piezo1在血流诱导淋巴生长和再生中的作用。发现Piezo1在淋巴内皮细胞（LECs）中大量表达。在培养的LECs中，Piezo1敲低抑制了层流诱导的钙内流，并取消了流介导的Orai1下游基因，如Klf2、Dtx1、Dtx3L和Notch1，这些基因参与淋巴萌发。相反，在没有流体流动的情况下，Piezo1的刺激激活了orai1调节的机械传导。Piezo1介导的机械转导被Orai1抑制显著阻断，建立了Piezo1和Orai1之间的上位性关系。在胚胎发育期间，淋巴特异性条件Piezo1敲除在Orai1或Klf2敲除淋巴中显示出大量表型的发芽缺陷。成人出生后缺失Piezo1诱导淋巴退化。异位Dtx3L的表达挽救了Piezo1基因敲除引起的淋巴缺陷，证实了Piezo1通过下调Notch促进淋巴萌发。一致地，转基因Piezo1表达或药理活化Piezo1促进淋巴发芽。最后，我们评估了Piezo1激活在淋巴再生中的潜在治疗价值，发现Piezo1激动剂Yoda1可以有效抑制术后淋巴水肿的发展。Piezo1是淋巴机械传导途径的上游机械传感器，在外部物理刺激下调节淋巴生长。Piezo1激活为预防术后淋巴水肿提供了一种新的治疗机会。piezo1调节的淋巴管生成机制为人类中与piezo1相关的淋巴畸形提供了分子基础。
Mutations in PIEZO1 cause human lymphatic malformations. We have previously uncovered an Orai1-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identify of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. Piezo1 was found to be abundantly expressed in lymphatic endothelial cells (LECs). Piezo1 knockdown in cultured LECs inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as Klf2, Dtx1, Dtx3L, and Notch1, which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed post-surgical lymphedema development. Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing post-surgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.
DOI：
10.1007/978-1-0716-2059-5_10
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
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通讯作者：
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