间充质干细胞 z-bo 2020-11-02 362

　　Extracellular vesicles (EV) are nano-sized vesicles released by normal and diseased cells. As a new form of intercellular communication, they can be used as effective therapeutic carriers for genes and drugs. However, the in vivo characteristics of EVs, such as tissue distribution, blood levels, and urine clearance, these important parameters that will determine its therapeutic effect and potential toxicity are still unknown.

　　MSC-EV distribution and metabolism in the body

　　"Mesenchymal stem cells (MSC) secrete a large number of EVs (MSC-EV), and the contents of MSC-EV include various proteins and RNA. In MSC-EV, most RNA (>80%); there are also some small RNAs, of which miRNA is about 44%, tRNA is about 47% [1]. At present, very few studies have focused on the distribution and metabolism of MSC-EV in the body.

　　The distribution of MSC-EV in the body is very similar to that of MSC, that is, after intravenous injection of MSC-EV, it is most distributed in the liver and spleen, and then dispersed to other tissues and organs. Interestingly, MSC has obvious lung retention, but the lung retention of MSC-EV is not obvious. In the lungs, intravenously infused MSC-EVs are almost undetectable, and EVs derived from human lung fibroblasts are likely to accumulate in the lungs.

　　"Bioluminescence and fluorescence-mediated tomography in mice showed that the main sites for intravenous injection of MSC-EV are liver, kidney and spleen.

　　EV was detected in the brain, heart, and muscle within 30 minutes after injection, and EV was detected in urine after 60 minutes; but after 6 hours, it was basically difficult to detect the input EV in the body.

　　In the mouse model experiment of acute kidney injury, after 24 hours of intravenous infusion of MSC-EV, in addition to accumulation in the liver and spleen, accumulation in the kidneys of acute kidney injury mice can also be observed, but not in the kidneys of the control group. The accumulation of MSC-EV.

　　Studies have also shown that MSC-EV can be detected in the body for more than 6 hours. Even after 48 hours of intravenous injection, the distribution signal intensity in the liver and spleen is still very strong.

　　After intravenous infusion of DID-labeled MSC-EV into the body, it is most distributed in the liver and spleen, less in the bone marrow of the spine, femur and tibia, and undetectable in the lungs, heart and kidneys; if the bone marrow is damaged by radiation, Then one hour after MSC-EV injection, MSC-EV accumulation in the injured bone marrow site can be detected, and the MSC-EV accumulated in the bone marrow does not decrease significantly within 24 hours [2]. This characteristic of MSC-EV is very similar to that of MSC, and it can actively chemoattract to the injury site and gather.

　　Researchers used PKH26 or CFSE-labeled EVs for in vivo tracking. EVs were identified and counted using flow cytometry, and Nanosight nanoparticle tracking analysis was used to measure size and morphology. They found that intravenously injected MSC-EV could migrate to infarcted ones. The brain, and the efficiency of MSC-EV through the blood-brain barrier exceeds that of MSC itself.

　　Interestingly, MSC-EV can also be modified like MSC. For example, the amount of MSC-EV modified with rabies virus glycoprotein (RVG) that migrates to the brain through tail vein injection into Alzheimer's mice is at least twice that of unmodified MSC-EV.

　　A research article mentions the uptake of MSC-EV by different cell types, that is, CD11b positive and F4/80 positive cells (monocytes/neutrophils/macrophages) uptake MSC-EV significantly, while B220 cells ( B lymphocytes) uptake of MSC-EV is not obvious.