What Is The Clinical Significance Of Extracellular Vesicles

Extracellular vesicles (EVs) are a general term for various vesicles with a lipid bilayer membrane structure that are released under resting or stress conditions. The diameter of the vesicles ranges from tens of nanometers to several micrometers. Almost all living cells release EV, which is found in various biological fluids such as blood, saliva, urine, and the extracellular environment. There is growing evidence that EVs contain maternal-related proteins (such as CD9, CD63, CD81, MHC-I, etc.), lipids, nucleotides, including DNA, messenger RNA (mRNA), microRNA (miRNA), circular RNA (cirRNA) and other non-coding RNAs, and a variety of biologically active substances, are widely involved in the transmission of information between cells through target cell internalization, receptor-ligand interaction or lipid membrane fusion. And they are essential for maintaining various physiological processes, such as immunosurveillance, coagulation, stem cell maintenance, and tissue repair, etc. In addition, studies have found that EV is also involved in a variety of pathological processes such as infectious diseases and inflammation, nervous system diseases and cancer, which can be used to monitor disease progression and therapeutic response, and can be developed into new drug carrier due to their ability to deliver biologically active substances.  The existence of these EVs provides a wealth of biological information for multi-faceted and multi-angle revealing disease occurrence and development mechanisms, and is expected to become a technology platform for biomedical research and application development.

In recent years, studies have found that mesenchymal stem cells (MSC)-derived EVs have similar biological effects as MSCs, such as reducing apoptosis, reducing inflammation, promoting angiogenesis, inhibiting fibrosis, and improving tissue repair potential. Extraction and transformation is easy, and tumor cell risk compared with stem cell transplantation are low, and have broad application prospects in the biological treatment of injury repair. In view of the important biological functions, broad research and application prospects of EV, the research on EV has grown exponentially in recent years, and has attracted extensive attention as an emerging field.

Classification, Production Mechanism and Characteristics of EV

Depending on the way, size or function of EV, it can be divided into exocytic originating from endocytic pathway, microvesicles released from plasma membrane and apoptotic bodies derived from apoptosis. The study found that the three EV subpopulations have different mechanisms of production. Exosomes originate from the endosomal system of cells. First, the cell membrane invades to form the primary endosomes, and the endosomal membrane re-invades to form a plurality of intraluminal vesicles. At this time, the endosomes containing multiple intraluminal vesicles, that is, the secondary endosomes are also called multivesicular bodies. The multivesicular body is an important protein transport and sorting center for eukaryotic cells. When the multivesicular body fuses with the cell membrane, the luminal vesicles in the sac are sag, and the granules are 30~120 nm in diameter by internal budding. Small vesicles are released into the extracellular environment, the exosomes. Microvesicles are large vesicles that protrude directly from the cytoplasmic membrane in a “outper” manner, with a diameter of 100 ~ 1000 nm. The cell membrane of the apoptotic cells is invaginated, and then segmented and encapsulated chromatin masses (nuclear fragments) and cytoplasm and then shed from the cells to form vesicles of varying sizes by means of budding or blistering, known as apoptotic bodies. In addition,  mitochondria, endoplasmic reticulum and other organelles in apoptotic cells and cytoplasmic components are encapsulated by endoplasmic reticulum membrane to form autophagosomes. After fusion with apoptotic cell membranes, apoptotic bodies can also be formed in vitro, with a diameter of 800 ~ 5000 nm.

Further studies have found that the composition of EV is not random, cells contain different EV contents in different states. Each EV carries specific molecular information. The unique molecular composition of the package determines the type of extracellular signaling to be delivered to the recipient cells,  and a complex sorting system determines which molecules can enter the extracellular vesicles. Researchers can collect the exocrine secreted by the cells to obtain the progression of disease , and then take effective measures for diagnosis and treatment. In addition, the use of autologous secreted exosomes to carry therapeutic drugs can both avoid immunogenicity and impart exosome targeting by modification. This is a potential nano drug carrier.