Veziroglu Eren M, Mias George I
Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States.
Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States.
Front Genet. 2020 Jul 17;11:700. doi: 10.3389/fgene.2020.00700. eCollection 2020.
Cells release nanometer-scale, lipid bilayer-enclosed biomolecular packages (extracellular vesicles; EVs) into their surrounding environment. EVs are hypothesized to be intercellular communication agents that regulate physiological states by transporting biomolecules between near and distant cells. The research community has consistently advocated for the importance of RNA contents in EVs by demonstrating that: (1) EV-related RNA contents can be detected in a liquid biopsy, (2) disease states significantly alter EV-related RNA contents, and (3) sensitive and specific liquid biopsies can be implemented in precision medicine settings by measuring EV-derived RNA contents. Furthermore, EVs have medical potential beyond diagnostics. Both natural and engineered EVs are being investigated for therapeutic applications such as regenerative medicine and as drug delivery agents. This review focuses specifically on EV characterization, analysis of their RNA content, and their functional implications. The NIH extracellular RNA communication (ERC) program has catapulted human EV research from an RNA profiling standpoint by standardizing the pipeline for working with EV transcriptomics data, and creating a centralized database for the scientific community. There are currently thousands of RNA-sequencing profiles hosted on the Extracellular RNA Atlas alone (Murillo et al., 2019), encompassing a variety of human biofluid types and health conditions. While a number of significant discoveries have been made through these studies individually, integrative analyses of these data have thus far been limited. A primary focus of the ERC program over the next five years is to bring higher resolution tools to the EV research community so that investigators can isolate and analyze EV sub-populations, and ultimately single EVs sourced from discrete cell types, tissues, and complex biofluids. Higher resolution techniques will be essential for evaluating the roles of circulating EVs at a level which impacts clinical decision making. We expect that advances in microfluidic technologies will drive near-term innovation and discoveries about the diverse RNA contents of EVs. Long-term translation of EV-based RNA profiling into a mainstay medical diagnostic tool will depend upon identifying robust patterns of circulating genetic material that correlate with a change in health status.
细胞会向周围环境释放纳米级、由脂质双层包裹的生物分子包（细胞外囊泡；EVs）。据推测，EVs是细胞间通讯介质，通过在近端和远端细胞之间运输生物分子来调节生理状态。研究界一直主张EVs中RNA含量的重要性，通过证明：（1）在液体活检中可检测到与EV相关的RNA含量，（2）疾病状态会显著改变与EV相关的RNA含量，以及（3）通过测量源自EV的RNA含量，可在精准医学环境中实施灵敏且特异的液体活检。此外，EVs在诊断之外还具有医学潜力。天然和工程化的EVs都在被研究用于再生医学等治疗应用以及作为药物递送载体。本综述特别关注EV的表征、其RNA含量分析及其功能意义。美国国立卫生研究院细胞外RNA通讯（ERC）项目通过规范处理EV转录组学数据的流程，并为科学界创建一个集中数据库，从RNA谱分析的角度推动了人类EV研究。仅细胞外RNA图谱目前就托管着数千个RNA测序图谱（穆里略等人，2019年），涵盖各种人类生物流体类型和健康状况。虽然通过这些单独的研究已经取得了许多重大发现，但迄今为止对这些数据的综合分析仍然有限。ERC项目未来五年的一个主要重点是为EV研究界带来更高分辨率的工具，以便研究人员能够分离和分析EV亚群，并最终分析源自离散细胞类型、组织和复杂生物流体的单个EV。更高分辨率的技术对于在影响临床决策的层面评估循环EVs的作用至关重要。我们预计微流控技术的进步将推动近期关于EVs多样RNA含量的创新和发现。将基于EV的RNA谱分析长期转化为主要的医学诊断工具将取决于识别与健康状态变化相关的循环遗传物质的稳健模式。
