What are Exosomes?

Exosomes are small extracellular vesicles that are released by various cell types including stem cells, immune cells, and cancer cells. They are believed to play a role in intercellular communication by transporting proteins, lipids and nucleic acids between cells.

Exosomes have been explored as a vehicle for drug delivery as they can cross biological barriers and target specific cell types of tissues. This approach has been studied for the treatment of various diseases including cancer neurological disorders and infectious diseases.

Research in this field is ongoing and there is a growing interest in developing methods to isolate, characterize, and manipulate exosomes for further clinical applications.

What are Exosomes?

Since the original recognition of these vesicles over 50 years ago, the term exosomes are a description of various forms of extracellular vesicles. These vesicles were originally thought to just be cellular debris. However, further research has implicated exosomes in the cell-to-cell communication. Therefore, exosomes can be considered as messengers between cells. Exosomes are best defined as extracellular vesicles that are released from cells upon the fusion of an endocytic compartment of the cell, a multivesicular body and the plasma membrane. This combination liberates these vesicles into the extracellular area and these vesicles are called exosomes.

Exosomes are of interest for 3 important reasons,

Exosomes are thought to provide a means of intercellular communication between cells.
Exosomes have been found to be involved in the spread of proteins, lipids, mRNA, and DNA and these substances are contributing factors in the development of some disease states.
Exosomes have been proposed to be useful vectors for drugs because they are composed of cell membranes and are better tolerated by the host.
Exosomes do not invoke an immune response.

How Are Exosomes Made?

Research has shown Exosomes are made from Intraluminal vesicles. This is a budding process that is not completely understood as not all intraluminal vesicles become exosomes. This is an unconventional budding process generated at the membrane and forms the exosomes.

Not all intraluminal vesicles become exosomes

All cells, prokaryotes and eukaryotes, release extracellular vesicles (EV) as part of their normal physiology and during acquired abnormalities. EV can be divided into two categories, ectosomes and exosomes. Ectosomes are vesicles that pinch off the surface of the plasma membrane via outward budding and include micro vesicles, microparticles and larger vesicles. Exosomes are EV with a small diameter with an endosomal origin. Sequential invagination of the plasma membrane ultimately results in the formation of multivesicular bodies which can interact with other intracellular vesicles and organelles, contributing to the diversity in the constituents of exosomes. Exosomes can contain many constituents of the cell including DNA, RNA, lipids, metabolites and cell proteins. It is speculated that exosomes likely remove excess and unnecessary constituents from cells to maintain cellular homeostasis. This creates a functional, targeted, mechanism driven accumulation of specific cellular components in exosomes, suggesting their role in the regulation of cellular communication.

The destiny of intraluminal vesicles is directed by the fate of the multivesicular bodies they live in. There are different types of multivesicular bodies and not all become exosomes.

MVB can fuse with lysosomes and the contents are degraded and recycled
Fuse with the cell membrane where ILV are released as exosomes
Contribute to specialized organelles such as melanosomes (in melanocytes), Weibel-Palade bodies (in endothelial cells) azurophilic granules (in neutrophils and secretory cells(in mast cells).
The level of cholesterol on multivesicular bodies appears to dictate the fate of these bodies where cholesterol rich MVB are directed to the cell membrane to become exosomes and cholesterol poor MVB are targeted to the lysosome for destruction and recycling.

Advances

Exosomes are associated with immune responses, viral pathogenicity, pregnancy, cardiovascular disease, central nervous system related diseases, cancer and many more. Proteins, metabolites and nucleic acids delivered by exosomes into recipient cells effectively alters their biological response. These intrinsic properties of exosomes in regulating complex intracellular pathways have advanced potential utility in the therapeutic control of many diseases. Exosomes can be engineered to deliver diverse therapeutic payloads to cells. The natural lipid and protein content of exosomes play a significant role in enhanced bioavailability and in minimizing adverse reactions.

Immune Responses

The role of exosomes in immune responses has now been widely documented. Engineered exosomes have indicated a function in eliciting adaptive and innate immune reactions

supporting their utility and a potential role in coordinating immune reactions in response to infection.

Seminal plasma derived exosomes inhibit HIV-1 infection, possibly by blocking HIV early protein activator and subsequent transcription of HIV-1.

Exosomes may also regulate the immune response by influencing gene expression and signaling pathways in recipient cells by modulating the transfer of mRNA.

Metabolic and Cardiac Diseases

Signaling between adipocytes and macrophages mediated by exosomes in a mouse model of obesity implicates insulin resistance. Obese mice fed a high fat diet display distinct exosomes sufficient to promote insulin resistance.

Cachexia, a condition of severe weight loss and muscle wasting may be exacerbated by cancer cell driven exosomes.

These findings support that cancer driven exosomes can change the metabolism of noncancer cells, including fat cells and muscle cells, thus functionally contributing to the development to muscle wasting in certain cancer states.

Conversely, exosomes can influence Leptin, develop insulin resistance and form obesity states.

The function of exosomes in preventing atherosclerosis was demonstrated where platelet derived exosomes reduced the uptake of harmful cholesterol thus promoting atherogenesis. The use of stem cell derived exosomes in cardiovascular disease has emerged as a potential therapeutic approach as these exosomes promote protective effects by limiting cardiomyocyte apoptosis, promoting mitochondrial function and preserving cardiac contractility.

Cancer

The study of exosomes in cancer has progressed at a rapid pace compared to research in other fields of medicine. Exosomes have been associated with several hallmark features of cancer as they influence neoplasia, tumor growth, metastasis and resistance to therapy. The role of exosomes is dynamic and specific to each cancer type making exosomes both a cause and a treatment.

Therapeutics and Drug Carriers

Exosomes have been recognized as potential therapeutic vehicles. They have the ability to elicit potent cellular responses. Exosomes can mediate regenerative outcomes in injury and disease states. Stem cell exosomes were found to activate multiple pathways critical in wound healing. Also, exosomes have been found to help with bone fracture repair and in the regulation of immune mediated responses and inflammatory diseases.

Exosomes are a promising carrier for effective delivery of drugs such as cancer immunotherapy and have provided excellent outcomes in several clinical trials. Composed of cellular membranes with multiple adhesive proteins on the surface, exosomes can provide an exclusive delivery system for various target cells and can increase the cytotoxicity to disease cells. In one

study of cancer cells, the drug delivered by the exosomes were 50 times more potent and delivered the drug almost exclusively to the targeted lung cancer cells.

Aesthetics

Exosomes represent a new and minimally invasive addition to the regenerative medical aesthetic toolbox. These vesicles contain bioactive molecules that have significant roles in intracellular communication. These vesicles target the causes of skin aging and improve the overall tissue homeostasis. Exosomes are an emergent therapy for skin rejuvenation and hair restoration.

Conclusion

Over the past few decades, the understanding of exosomes has been greatly expanded. Exosomes, once thought to be cellular garbage, are now considered a diagnostic and therapeutic tool. With the advent of high sensitivity exosome isolation and purification protocols, this evolving field will continue to make a huge impact on the healthcare field now and in the future.

Regenerative Regards,

Dr. Robert McGrath

References