Exosomes: Fit to deliver small RNA.
Exosomes: Fit to deliver small RNA.
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DOI：
10.4161/cib.3.5.12339
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发表时间：
2010-09
影响因子：
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通讯作者：
A. Zomer;Tineke Vendrig;Erik S. Hopmans;M. V. van Eijndhoven;Jaap M Middeldorp;D. Pegtel
中科院分区：
文献类型：
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作者：
A. Zomer;Tineke Vendrig;Erik S. Hopmans;M. V. van Eijndhoven;Jaap M Middeldorp;D. Pegtel
外泌体是来源于由许多细胞类型释放的内吞隔室的特化膜状纳米尺寸囊泡。微泡与外来体的区别在于它们是通过质膜脱落产生的，并且通常尺寸较大（>1 µm）。外泌体生物发生涉及从多泡体（MVB）的界膜向内出芽的严格控制的过程。这导致在MVB的管腔中存在许多管腔内囊泡，其含有不同的蛋白质组库。已经表明，由某些肿瘤细胞脱落的微泡含有可能促进肿瘤进展的功能性信使RNA（mRNA）。我们发现，纯化的exosomes含有功能性microRNA（miRNAs）和小RNA，但检测到很少的mRNA。虽然微囊泡和外来体之间不能进行明确和决定性的区分，并且存在外来体的不同子集，但我们推测外来体专门携带小RNA，包括22-25类核苷酸调节miRNA。为了证明这一点，我们开发了共培养系统，并发现外泌体从Epstein巴尔病毒（EBV）感染的细胞连续分泌并转移到未感染的邻近细胞。在整个外泌体转移过程中，外源EBV编码的miRNA被递送到miRNA介导的基因阻遏的亚细胞位点。此外，我们发现了成熟miRNA在人类循环细胞之间转移的证据，因为我们在患者外周血中的未感染细胞中检测到EBV-miRNA，包括单核细胞和T细胞。在本附录中，我们讨论了这些发现的背景下，最近发表的论文，推进我们目前的知识外泌体生理学，（中）RNA功能和细胞间RNA转移。基于这些信息，我们提出细胞间（基于miRNA）的信号传递模式可能非常适合于控制空间受限的过程，例如次级（外周）淋巴组织或肿瘤微环境中免疫反应的启动。破译控制小RNA加载到外泌体中并在体外转移到受体细胞的分子机制将为体内囊泡介导的细胞间通讯的生理相关性提供新的证据。
Exosomes are specialized membranous nano-sized vesicles derived from endocytic compartments that are released by many cell types. Microvesicles are distinctive from exosomes in that they are produced by shedding of the plasmamembrane and usually larger in size (>1 µm). Exosome biogenesis involves the tightly controlled process of inward budding from the limiting membrane of multivesicular bodies (MVBs). This results in numerous intraluminal vesicles in the lumen of MVBs that contain distinct protein repertoires. It has been suggested that microvesicles shed by certain tumor cells hold functional messenger RNA (mRNA) that may promote tumor progression. We discovered that purified exosomes contain functional microRNAs (miRNAs) and small RNA, but detected little mRNA. Although a clear and decisive distinction between microvesicles and exosomes cannot be made and different subsets of exosomes exist, we speculate that exosomes are specialized in carrying small RNA including the class 22-25 nucleotide regulatory miRNAs. To demonstrate this we developed a co-culture system and found that exosomes are continuously secreted and transferred from Epstein Barr virus (EBV)-infected cells to uninfected neighboring cells. Throughout exosome transfer, the exogenous EBV-encoded miRNAs were delivered to subcellular sites of miRNA-mediated gene repression. Additionally, we found evidence that mature miRNAs are transferred between circulating cells in humans, since we detected EBV-miRNAs in non-infected cells in the peripheral blood of patients that include monocytes and T cells. In this addendum we discuss these findings in the context of recently published papers that advanced our current knowledge of exosome physiology, (mi)RNA function and intercellular RNA transfer. Based on this information we propose that an intercellular (miRNA-based) mode of signal transmission may be well suited in controlling space-confined processes such as the initiation of immune responses in the secondary (peripheral) lymphoid tissues or in a tumor microenvironment. Deciphering the molecular mechanism(s) that control small RNA loading into exosomes and transfer to recipient cells in vitro will provide new evidence for the physiological relevance of vesicle-mediated intercellular communication in vivo.