Piezo1 调节的机械转导控制流动激活的淋巴扩张。
Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
机构信息
Department of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
出版信息
Circ Res. 2022 Jul 8;131(2):e2-e21. doi: 10.1161/CIRCRESAHA.121.320565. Epub 2022 Jun 14.
BACKGROUND
Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity 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.
METHODS
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.
RESULTS
Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), 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 postsurgical lymphedema development.
CONCLUSIONS
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 postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.
背景
PIEZO1（机械敏感离子通道成分 1 型）中的突变会导致人类淋巴管畸形。我们之前发现了一种 ORAI1（ORAI 钙释放激活钙调制器 1）介导的机械转导途径，该途径通过 Notch 下调响应流体流动触发淋巴管发芽。然而，其上游机械感受器的身份仍然未知。本研究旨在鉴定和表征将流体介导的外部信号转换为 Orai1 调节的淋巴管扩张的分子传感器。
方法
使用各种突变小鼠模型、细胞、生化和分子生物学工具以及小鼠尾淋巴水肿模型，阐明 Piezo1 在流诱导的淋巴生长和再生中的作用。
结果
发现 Piezo1 在淋巴管内皮细胞中大量表达。在培养的淋巴管内皮细胞中敲低 Piezo1 会抑制层流诱导的钙内流，并阻断 Piezo1 下游基因（如 KLF2（Krüppel 样因子 2）、DTX1（Deltex E3 泛素连接酶 1）、DTX3L（Deltex E3 泛素连接酶 3L）和 NOTCH1（Notch 受体 1））的流动调节，这些基因参与淋巴管发芽。相反，Piezo1 的刺激在没有流体流动的情况下激活了 Orai1 调节的机械转导。Orai1 抑制显著阻断 Piezo1 介导的机械转导，确立了 Piezo1 和 Orai1 之间的上位关系。淋巴特异性条件性 Piezo1 敲除在胚胎发育过程中在很大程度上模拟了 Orai1 或 Klf2 敲除淋巴中的发芽缺陷。成年后 Piezo1 的缺失诱导淋巴管退化。异位 Dtx3L 表达挽救了 Piezo1 缺失引起的淋巴管缺陷，证实 Piezo1 通过 Notch 下调促进淋巴管发芽。一致地，转 Piezo1 表达或药理学 Piezo1 激活增强了淋巴管发芽。最后，我们评估了 Piezo1 激活在淋巴再生中的潜在治疗价值，并发现 Piezo1 激动剂 Yoda1 有效抑制了术后淋巴水肿的发展。
结论
Piezo1 是淋巴机械转导途径的上游机械感受器，调节淋巴对外部物理刺激的生长。Piezo1 的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 Piezo1 相关淋巴管畸形提供了分子基础。
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