Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.

IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING
Alexandra E Johns, Arens Taga, Andriana Charalampopoulou, Sarah K Gross, Khalil Rust, Brett A McCray, Jeremy M Sullivan, Nicholas J Maragakis
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Abstract

ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.

探索在 hiPSC 运动神经元模型中将 P2X7 受体拮抗作为神经保护的治疗靶点。
ATP 在健康组织间质中的浓度可忽略不计,但在炎症微环境中会蓄积到明显更高的浓度。ATP 与细胞表面的两类嘌呤受体结合,即离子型 P2X 受体和代谢型 P2Y 受体。离子型嘌呤受体家族中包括 P2X7(P2X7R),它是一种非特异性阳离子通道,具有独特的功能和结构特性,表明它在细胞外 ATP 增高的病理条件下具有独特的作用。P2X7R 的作用以前曾在神经炎症的背景下在小胶质细胞和星形胶质细胞中进行过探讨,但 P2X7R 在人类运动神经元中的存在及其在神经退行性疾病中的潜在作用还不是目前文献研究的重点。我们利用人类 iPSC 衍生的脊髓运动神经元(hiPSC-MN)以及人类和啮齿动物组织证明了 P2X7R 在运动神经元上的表达。我们扩展了这一观察结果,证明这些受体在 hiPSC-MN 上具有功能活性,并且 ATP 可以通过 P2X7R 激活以剂量依赖性方式直接诱导死亡。最后,我们利用一种高度特异性的 P2X7R 阻断剂,证明了调节运动神经元上的 P2X7R 激活如何具有神经保护作用,并为 ATP 诱导的 MN 死亡提供了一个独特的药理学靶点,它不同于 ATP 作为神经炎症调节剂的作用。
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来源期刊
Stem Cells Translational Medicine
Stem Cells Translational Medicine CELL & TISSUE ENGINEERING-
CiteScore
12.90
自引率
3.30%
发文量
140
审稿时长
6-12 weeks
期刊介绍: STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal. STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes. The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.
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