Exosome therapy is one of the novel therapies that are expected to become available in the future, but it is currently in the research stage.
Only after basic research and clinical studies are conducted and its efficacy is confirmed will it be offered as a treatment covered by insurance.
The current paper is the first step in this process, using an animal model to verify the therapeutic effect of exosomes on spinal cord injury. Exosomes are derived from bone marrow mesenchymal stem cells, the most commonly used stem cell therapy research.
Let’s take a quick look at it.
Nakazaki, M., et al., 2021. Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF-beta upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury. J Extracell Vesicles. 10, e12137.
Brief description.
Bone marrow mesenchymal stem cell-derived exosomes (MSC-sEVs) have a therapeutic effect on spinal cord injury comparable to MSC cell therapy.
Intravenous injection of MSC-sEVs improves functional recovery in models of spinal cord injury by transporting them to the site of injury and binding to M2 macrophages.
To achieve the same therapeutic effect as a single injection of MSC cells, MSC-sEVs must be administered in divided doses over 3 days. This is because in a single dose of exosomes, the exosomes are not taken up by the lesion and are largely expelled.
In MSC cells, exosomes are released over time and a series of cellular responses occur that lead to improved functional recovery. It has been shown that a similar response can be induced by exosome fractionation.
Term Description.
Bone marrow mesenchymal stem cell
Bone Marrow Mesenchymal Stem Cells (BMSCs) are a specialized type of cell found in the bone marrow. These cells are multifunctional and have the ability to differentiate into many different cell types, including bone, cartilage, muscle, fat, and connective tissue.
The primary role of bone marrow mesenchymal stem cells is to produce the necessary cells to compensate for loss when damage or aging occurs in the body. They also have immunomodulatory and anti-inflammatory functions, and play a role in reducing inflammation in the body and maintaining the balance of the immune system.
In recent years, bone marrow mesenchymal stem cells have attracted a great deal of attention and research in the field of regenerative medicine. In the future, they are expected to be useful in the treatment of various diseases and injuries.
Exosomes
Exosomes are very small sized extracellular vesicles (approximately 30-150 nanometers) secreted by cells that play an important role in cell-to-cell communication. Exosomes are produced by the inner membrane system within the cell and released outside the cell.
Inside exosomes are a wide variety of biological molecules, including proteins, lipoproteins, lipids, sugars, and nucleic acids (DNA and RNA). These molecules act as “messengers” that allow the exosome to share information with other cells. The uptake of exosomes by their target cells can alter the function and fate of the receiving cells.
Exosomes are involved in a variety of biological processes, including immunomodulation, cell proliferation, cell death, and inflammation. In recent years, exosomes have also been implicated in cancer cell proliferation and metastasis, and have attracted much attention in the field of cancer research.
Exosomes also have potential as a regenerative medicine and diagnostic tool. Research is underway to develop therapies using exosomes and to use biological molecules contained in exosomes as diagnostic markers.
M2 Macrophages
M2 macrophages (M2 macrophages, M2 macrophages) are a type of white blood cell that is part of the immune system and are a type of macrophage with tissue repair and anti-inflammatory properties. Macrophages are also known as “phagocytes” that eliminate pathogens such as bacteria and viruses from the body by eating them.
Macrophages are mainly classified into M1 macrophages and M2 macrophages based on their function: M1 macrophages promote an inflammatory response and work to eliminate pathogens and cancer cells, while M2 macrophages suppress the inflammatory response and promote tissue repair and remodeling.
M2 macrophages play important roles in a variety of diseases and conditions. For example, in diseases such as chronic inflammation, autoimmune diseases, allergies, infectious diseases, and cancer, suppressing inflammation may relieve symptoms and promote tissue repair. However, in some diseases, overactivation of M2 macrophages may promote disease progression.
In recent years, therapies targeting M2 macrophages have been developed. For example, in cancer therapy, it is expected to slow the progression of cancer by suppressing the ability of M2 macrophages to help cancer cells proliferate and metastasize. Also, in chronic inflammatory and autoimmune diseases, treatments utilizing the anti-inflammatory effects of M2 macrophages are being investigated.
What kind of results were obtained?
The results of this paper suggest that exosomes (MSC-sEVs) released over time from mesenchymal stem/stromal cells (MSCs) induce a series of cellular responses that lead to improved functional recovery in experimental models of spinal cord injury (SCI). These exosomes were incorporated into M2 macrophages, leading to increased expression of transforming growth factor-beta (TGF-beta), followed by upregulation of TGF-beta receptors and numerous proteins related to the function of the microvasculature around SCI, ultimately leading to functional stabilization of spinal cord microvasculature To achieve the same therapeutic effect as a single MSC injection, MSC-SEV had to be administered in divided doses over 3 days. Intravenous injection of fractionated MSC-exosomes mimicked the effects of single MSC cell administration on several parameters, including increased expression of M2 macrophage markers, upregulation of TGF-β, TGF-β receptors, and proteins related to microvasculature function, and decreased permeability of spinal cord microvessels. The results of this study are shown in Figure 1.
Reference; Disruption of microvasculature around spinal cord injury (blood-spinal cord barrier) is thought to be associated with secondary injury in spinal cord injury.
The red inverted triangle represents the exosome fractionated administration group. The blue circle represents the MSC cell administration group, the green triangle represents the single-dose exosome administration group, and the gray square represents the untreated rat group. When administering the same amount of exosomes, dividing it into three doses and administering it over three days had a higher therapeutic effect compared to a single dose. The fractionated administration of exosomes achieves the same effect as cell therapy. Exosome therapy holds promise for future development due to its higher safety and potential for advancement compared to cell therapy.
What are the limitations of this study?
This study was conducted on rats, and it is unclear whether the results can be applied to humans. Additionally, the underlying mechanism behind the therapeutic effects of MSC-exosomes has not been fully elucidated and further investigation is needed. Specifically, determining the optimal dosage and timing of MSC-exosome administration is necessary. Moreover, the long-term impact and potential side effects of MSC-exosome therapy on spinal cord injury (SCI) recovery need to be evaluated. The study did not investigate the effects of MSC-exosomes on other cell types involved in SCI, such as oligodendrocytes and neurons.
Future directions of this research?
Improvements in the dosage and administration methods of MSC-exosomes are necessary. Further studies are needed to assess whether extending the treatment period through additional injections or osmotic pump delivery can further enhance recovery. Additionally, further in vitro and in vivo studies are needed to understand how MSC-exosomes affect the function of macrophages.
My insights
MSC cell therapy has a history and has been the subject of extensive basic research. Its clinical applications have also advanced. However, its therapeutic mechanisms are not yet clearly understood. This paper suggests the possibility that MSC cells, when transplanted intravenously, may demonstrate therapeutic effects through exosomes. Furthermore, the administration of exosomes through intravenous injection yielding similar therapeutic effects implies that the exosomes themselves contain some therapeutic elements, suggesting that exosomes themselves could be potential novel therapeutics. Future research is awaited to determine the contents of these exosomes, the molecular changes they induce after uptake by macrophages in the vicinity of the spinal cord injury site, and their implications.
