Multiomics analysis reveals the mechanical stress-dependent changes in trabecular meshwork cytoskeletal-extracellular matrix interactions.
Multiomics analysis reveals the mechanical stress-dependent changes in trabecular meshwork cytoskeletal-extracellular matrix interactions.
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多组学分析揭示了小梁网细胞骨架-细胞外基质相互作用中机械应力依赖性变化。
DOI：
10.3389/fcell.2022.874828
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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由于心动周期产生的眼脉冲，小梁网（TM）组织受到恒定的机械应力。这引起膜脂质和相关的细胞-细胞粘附和细胞-细胞外基质（ECM）相互作用的改变，触发细胞内信号传导应答以对抗机械损伤。这种反应的丧失可导致眼内压（IOP）升高，这是原发性开角型青光眼的主要危险因素。本研究的目的是了解TM受到机械拉伸的信号反应的变化。我们利用多组学进行无偏的mRNA测序，以确定转录物的变化，基于质谱（MS）的定量蛋白质组学的蛋白质变化，多反应监测（MRM）的分析为基础的MS和高效液相色谱（HPLC）为基础的MS来表征脂质的变化。我们进行了途径分析，以获得一个完整的地图TM响应机械拉伸。经受机械拉伸的人TM细胞表现出蛋白质质量控制、氧化损伤反应、促自噬信号、抗凋亡诱导和存活信号传导的上调。我们认为，机械拉伸诱导的脂质信号通过增加神经酰胺和鞘磷脂可能有助于增加TM刚度通过肌动蛋白细胞骨架重组和促纤维化反应。有趣的是，由于机械拉伸而增加的磷脂和甘油二酯可能使细胞膜重塑和信号通路的变化改变细胞收缩性。总的来说，我们提出了大分子的机械相互作用，使一个协调一致的细胞反应，在TM细胞，以实现机械转导和眼压调节时，TM细胞进行机械拉伸。
Trabecular meshwork (TM) tissue is subjected to constant mechanical stress due to the ocular pulse created by the cardiac cycle. This brings about alterations in the membrane lipids and associated cell–cell adhesion and cell–extracellular matrix (ECM) interactions, triggering intracellular signaling responses to counter mechanical insults. A loss of such response can lead to elevated intraocular pressure (IOP), a major risk factor for primary open-angle glaucoma. This study is aimed to understand the changes in signaling responses by TM subjected to mechanical stretch. We utilized multiomics to perform an unbiased mRNA sequencing to identify changes in transcripts, mass spectrometry- (MS-) based quantitative proteomics for protein changes, and multiple reaction monitoring (MRM) profiling-based MS and high-performance liquid chromatography (HPLC-) based MS to characterize the lipid changes. We performed pathway analysis to obtain an integrated map of TM response to mechanical stretch. The human TM cells subjected to mechanical stretch demonstrated an upregulation of protein quality control, oxidative damage response, pro-autophagic signal, induction of anti-apoptotic, and survival signaling. We propose that mechanical stretch-induced lipid signaling via increased ceramide and sphingomyelin potentially contributes to increased TM stiffness through actin-cytoskeleton reorganization and profibrotic response. Interestingly, increased phospholipids and diacylglycerol due to mechanical stretch potentially enable cell membrane remodeling and changes in signaling pathways to alter cellular contractility. Overall, we propose the mechanistic interplay of macromolecules to bring about a concerted cellular response in TM cells to achieve mechanotransduction and IOP regulation when TM cells undergo mechanical stretch.