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Reviewed by Inna Gordiienko, biologist of biotechnology laboratory, PhD.
Written by Viktoria Kosiak, biologist assistant, biophysicist
Today, exosomes are a promising tool for the treatment of many diseases. Among their advantages: high bioavailability, a wide range of impact tools, marked regenerative effects. At the same time, the following questions are quite common:● What is the mechanism of exosomes action obtained from MSCs in tissue and organ damage?● Is it safe to use exosomes?● What therapeutic properties make exosomes an interesting tool for physicians in combating many diseases?
We are going to answer all these questions in this article.
The instructions to any pharmacological drug describe the path of its metabolism by the body, ie the following parameters:1. To which organs does the drug get first?2. After what time does it have its maximum effectiveness?3. What is the way of transformation and excretion of the drug?
Although biotechnological products do not belong to the classic pharmacological drugs and belong to the advanced therapy medicinal products according to the classification of the European Medicines Agency (EMA), the issue of pharmacokinetics is important for understanding their effects on the body. A number of preclinical studies in animal models have shown that in the case of intravenous administration, the largest proportion of exosomes (70-95%) within the first 30 minutes leaves the bloodstream. One hour after systemic administration, exosomes are not detected in the bloodstream. Reallocation of exosomes in the body occurs in at least three phases:● fast (less than an hour);● average (from 2 to 12 hours);● late (over 24 hours).
The liver, spleen, lungs, and kidneys are the organs where exosomes enter first. The highest concentration of exosomes when administered intravenously is detected in the liver, and their number remains consistently high for 24 hours. Low concentration of exosomes is detected in the following organs:● hearts;● brain;● bones;● gastrointestinal tract in the middle phase of reallocation.
This reallocation of exosomes after systemic administration can be partly explained by the peculiarities of the cellular and molecular composition of both exosomes and target organs. For example, the accumulation of exosomes in the liver is due to the presence of Kupffer cells — specialized macrophages that absorb exosomes the most. In the lungs, exosomes are absorbed by fibroblasts and epithelial cells. This depends on the presence on the exosomes surface of special molecules — α6β1 integrins. Excretion of exosomes from the body occurs through the kidneys and liver.
The use of exosomes by local injections predominates in clinical trials. A limited number of clinical results have been published with intravenous administration. However, intravenous administration of high concentrations of exosomes (from 10 billion per ml) has been shown to be easily tolerated by patients and to be effective in overcoming the severe course of COVID-19.
Exosomes derived from MSCs transmit information to recipient cells in several possible ways:
1. Direct interaction of the exosome receptor with the receptor on the plasma membrane of the recipient cell, which will initiate the appropriate signaling pathway.
2. Merging of the exosomes membrane with the recipient cell membrane and the subsequent release of its contents into the cytoplasm.
3. Capture (internalization) of exosomes by the cell in different ways (clathrin / caveolin-mediated endocytosis, phagocytosis, micropinocytosis).
Internalization of exosomes occurs rapidly and is temperature dependent. The content of exosomes can get into the cytoplasm and cytoplasmic compartments (endoplasmic reticulum, Golgi complex, late endosomes, lysosomes). In addition, it was detected that exosomes are able to recirculate from one cell to another, penetrating not only the surface but also deep layers of tissue. Growth factors contained in exosomes are more stable and last longer than those that enter the cell without the participation of exosomes. Merging of exosomes with lysosomes that have an acidic medium promotes the activation of some signaling molecules, such as TGFβ-1, and merging with late endosomes accelerates the release of exosomes into the cytoplasm. Exosomes miRNA, entering the cytoplasm, find their target mRNA molecule and block protein synthesis from it, thereby acting as a regulator of gene expression in the recipient cell. Thus, the ways in which exosomes enter cells are different, and the ways in which the informative message of exosomes is realized are also different.
What about the toxicity of exosomes derived from MSCs? After all, many cosmetic agents of biological origin can cause irritation or other more serious allergic reactions.
A large-scale study was conducted to assess the toxicity of exosomes derived from MSCs. Its purpose was to assess the toxicological profile of exosomes from adipose tissue MSCs, including the following indicators:
● ability to sensitize the skin;
● ability to photosensitize;
● eye irritation;
● skin irritation;
● as well as acute oral toxicity.
Scientists evaluated all parameters in accordance with the OECD (Organization for Economic Cooperation and Development) recommendations and the GLP (Good Laboratory Practice) principles. The study concludes that exosomes derived from MSCs:
1. Were classified as substances that are potentially incapable of sensitizing the skin in a skin sensitization test.
2. Did not receive any category in the eye irritation test.
3. Do not irritate the skin in the test for skin irritation.
4. Did not cause phototoxicity.
5. Did not cause a reaction in the test for acute oral toxicity.
The researchers conclude that MSC exosomes are safe for topical use, have no side effects during toxicological testing, and have the potential to be used as a therapeutic agent, cosmetic ingredient, or other therapeutic purpose.
For large-scale production, exosomes are obtained from donor MSCs, so patients and doctors question the possible response from the immune system. Comprehensive proteomic analysis of exosomes derived from MSCs did not reveal the presence of molecules of the major histocompatibility complex (MHC) types I and II, which are the main inducers of the immune response during transplantation. More than 200 different animal studies using human MSC exosomes have not reported immune responses. In addition, studies using repeated doses of exosomes also did not reveal changes in hematological parameters and histological sections of tissues of various organs. Therefore, exosomes can be defined as hypoimmunogenic, like their producing cells, MSCs.
1. Anti-inflammatory.Exosomes isolated from MSCs are able to reduce the expression of inflammatory proteins such as TNF-α, IL-1β, MMPs. At the same time, they promote the synthesis of anti-inflammatory proteins IL-4, IL-10 and TIMPs. Due to these properties, exosomes effectively reduce inflammation, which is necessary for rapid recovery of damaged tissue. Also, their use can improve the condition of the body in autoimmune diseases and conditions accompanied by excessive immune response.
2. Antioxidant.Peroxidase contained in exosomes can reduce the effects of oxygen under oxidative stress. This phenomenon is characteristic of many diseases and plays a key role in tissue degeneration during aging. Reducing oxidative stress promotes better cell survival and function.
3. Antiapoptotic.Antiapoptotic proteins in exosomes are able to stop cell death, which is important in overcoming various degenerative processes.
4. Antifibrous.Exosomes with MSCs provide normal reorganization of damaged skin due to induction of type I / III collagen synthesis. Reducing fibrosis during wound healing or recovery from injury increases the likelihood of normal tissue formation without scarring.
5. Proangiogenic.Exosomes isolated from MSCs are able to activate endothelial cells and thus stimulate angiogenesis. Improving blood circulation in trauma-damaged or diseased tissues increases cell survival and prevents their degradation by increasing the supply of nutrients and oxygen.
6. Stimulation of collagen and intercellular matrix synthesis.MSC exosomes activate fibroblasts. This helps increase the synthesis of the intercellular matrix, repair damaged tissues and prevent aging of the skin. Specific exosomal miRNAs help restore normal collagen levels and stimulate cartilage regeneration.
7. Epigenetic reactivation of cells.Exosomal proteins such as histone deacetylase can induce transcription of inactive DNA and affect cell function without interfering with the genome directly. This is how the activity of the desired genes can be restarted.
Given these distinctive therapeutic features, it is not surprising that MSC exosomes are now the subject of many preclinical and clinical studies. Some of them we are going to discuss in the next publication. Please follow our news.
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Sources:1. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. 2020 Jun 15;29(12):747-754. doi: 10.1089/scd.2020.0080. Epub 2020 May 12. PMID: 32380908; PMCID: PMC7310206.ahttps://pubmed.ncbi.nlm.nih.gov/32380908/ 2. Ha DH, Kim SD, Lee J, Kwon HH, Park GH, Yang SH, Jung JY, Lee JH, Park SR, Youn J, Lee SH, Kim JE, Lim J, Lee HK, Cho BS, Yi YW. Toxicological evaluation of exosomes derived from human adipose tissue-derived mesenchymal stem/stromal cells. Regul Toxicol Pharmacol. 2020 Aug;115:104686. doi: 10.1016/j.yrtph.2020.104686. Epub 2020 May 22. PMID: 32450131.https://pubmed.ncbi.nlm.nih.gov/32450131/ 3. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021 Apr 23;19(1):47. doi: 10.1186/s12964-021-00730-1. PMID: 33892745; PMCID: PMC8063428.https://doi.org/10.1186/s12964-021-00730-1 4. Kang, M., Jordan, V., Blenkiron, C., & Chamley, L. W. (2021). Biodistribution of extracellular vesicles following administration into animals: A systematic review. J. Extracell. Vesicles, 00, e12085. https://doi.org/10.1002/jev2.12085