Demystifying the long noncoding RNA landscape of small EVs derived from human mesenchymal stromal cells.
Demystifying the long noncoding RNA landscape of small EVs derived from human mesenchymal stromal cells.
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揭秘来源于人类间充质基质细胞的小EV的长非编码RNA景观。
DOI：
10.1016/j.jare.2021.11.003
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发表时间：
2022-07
影响因子：
10.7
通讯作者：
Lee, Oscar Kuang-Sheng
中科院分区：
文献类型：
--
作者：
Lee, Chien-Wei;Chen, Yi-Fan;Hsiao, Allen Wei-Ting;Wang, Amanda Yu-Fan;Shen, Oscar Yuan-Jie;Wang, Belle Yu-Hsuan;Ho, Lok Wai Cola;Lin, Wei-Ting;Choi, Chung Hang Jonathan;Lee, Oscar Kuang-Sheng
细胞类型特异性协调了小型EV（sEV）中的lncRNA特征。sEV中的LncRNA模式与其亲本细胞不同。MSC-sEV特异性和富集的lncRNA被鉴定为药物信号lncRNA。MSC-sEV的lncRNA景观对炎性细胞因子有反应。lncRNA-蛋白质相互作用体与核活性和染色质重塑相关。间充质基质细胞或药物信号细胞（MSC）的再生能力主要由其分泌的小细胞外囊泡（sEV）介导，并且sEV的治疗功效可以通过许可方法（例如，细胞因子、缺氧、化学品和遗传修饰）。已证明MSC衍生的sEV（MSC-sEV）内的非编码RNA负责组织再生。然而，与已被探索的miRNA指纹不同，MSC-sEV中长链非编码RNA（lncRNA）的情况仍有待描述。在有或没有炎性细胞因子许可的情况下表征人脂肪来源的MSC的sEV中的lncRNA特征，并描述MSC-sEV特异性和MSC富集的lncRNA库。在有或没有TNF-α和IFN-γ（20 ng/mL）刺激的情况下从MSC分离sEV。采用高通量lncRNA测序和计算机模拟方法分析sEV中lncRNA的谱并预测lncRNA-蛋白质相互作用组。来源于人MSC和成纤维细胞的sEV携带与这些细胞内的lncRNA不同的lncRNA的独特景观。与成纤维细胞来源的sEV（F-sEV）相比，MSC-sEV中194个MSC-sEV特异性lncRNA和8个上调的lncRNA被认为是“药物信号lncRNA”; MSC-sEV中炎性细胞因子上调27个lncRNA，被认为是“许可反应lncRNA”。基于lncRNA-protein interactome的预测和富集分析，我们发现与药物信号lncRNA或许可响应lncRNA相互作用的蛋白质具有紧密的相互作用网络，涉及染色质重塑、SWI/SNF超家族类型复合物和组蛋白结合。总之，我们的研究描绘了MSC-sEV中lncRNA的景观，并通过lncRNA-蛋白质相互作用组预测了它们的潜在功能。阐明MSC-sEV的lncRNA景观将有助于确定MSC-sEV的治疗效力和基于sEV的治疗剂的开发。
Cell-type specificity orchestrates the lncRNA signatures in small EVs (sEVs). LncRNA pattern in sEVs is distinct from their parental cells. MSC-sEV-specific and enriched lncRNAs were identified as medicinal signaling lncRNAs. lncRNA landscape of MSC-sEVs is responded to inflammatory cytokines. lncRNA-protein interactome associates with nuclear activity and chromatin remodeling. The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described. To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires. sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes. sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered “medicinal signaling lncRNAs”; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered “licensing-responsive lncRNAs”. Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding. In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics.
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