Exosome therapy is one of the promising novel treatments of the future, but it is currently still at the research stage.
Only after efficacy is confirmed through basic research and clinical research will treatment be offered as insured medical care.
This time, the paper verifies the therapeutic effect of exosomes on spinal cord injury using an animal model, which is the very first step. The exosomes are derived from bone marrow mesenchymal stem cells, the cells most widely used in stem cell therapy research.
So let’s get right into it.
The paper introduced this time
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.
Explanatory video;
In brief
- Bone marrow mesenchymal stem cell-derived exosomes (MSC-sEVs) have a therapeutic effect on spinal cord injury equivalent to that of MSC cell therapy.
- Intravenous injection of MSC-sEVs is transported to the injury site and binds to M2 macrophages, thereby improving functional recovery in a spinal cord injury model.
- To obtain a therapeutic effect similar to a single injection of MSC cells, the MSC-sEVs must be administered in divided doses over three days. This is because, with a single dose of exosomes, most of the exosomes are excreted without being taken up by the lesion.
- In MSC cells, exosomes are released over time, triggering a series of cellular responses that lead to improved functional recovery. It was shown that divided-dose administration of exosomes induces a similar response.
Explanation of terms
Bone marrow mesenchymal stem cells
Bone marrow mesenchymal stem cells (Bone Marrow Mesenchymal Stem Cells) are a type of specialized cell present within the bone marrow. These cells are multifunctional and have the ability to differentiate into various types of cells, such as bone, cartilage, muscle, fat, and connective tissue.
The main role of bone marrow mesenchymal stem cells is to generate the cells needed to compensate for losses when injury or aging occurs in the body. They also possess immunomodulatory and anti-inflammatory functions, playing a role in suppressing inflammation in the body and maintaining the balance of the immune system.
In recent years, bone marrow mesenchymal stem cells have attracted great attention in the field of regenerative medicine, and research is underway. In the future, they are expected to be useful in the treatment of various diseases and injuries.
Exosomes (exosomes)
Exosomes (exosomes) are very small extracellular vesicles secreted by cells (approximately 30-150 nanometers) that play an important role in cell-to-cell communication. Exosomes are generated from the endomembrane system inside the cell and released to the outside of the cell.
Inside exosomes are a diverse array of biological molecules, including proteins, lipoproteins, lipids, sugars, and nucleic acids (DNA and RNA). These molecules act like “messengers” through which exosomes share information with other cells. When an exosome is taken up by a target cell, the function or fate of the recipient cell can change.
Exosomes are involved in various biological processes such as immune regulation, cell proliferation, cell death, and inflammation. In addition, in recent years it has become clear that exosomes are involved in the proliferation and metastasis of cancer cells, and they are attracting attention in the field of cancer research.
Exosomes also hold potential as a tool for regenerative medicine and diagnosis. Research is underway on therapies that use exosomes and on using the biological molecules contained in exosomes as diagnostic markers.
M2 macrophages
M2 macrophages (M2 macrophages) are a type of leukocyte that is part of the immune system, and among macrophages they are a type of cell with particular tissue-repair and anti-inflammatory functions. Macrophages are also known as “phagocytes,” which eliminate pathogens such as bacteria and viruses from the body by eating them.
Macrophages are classified mainly into M1 macrophages and M2 macrophages according to their function. M1 macrophages promote inflammatory responses and work to eliminate pathogens and cancer cells, whereas M2 macrophages suppress inflammatory responses and promote tissue repair and remodeling.
M2 macrophages play important roles in various diseases and conditions. For example, in diseases such as chronic inflammation, autoimmune diseases, allergies, infections, and cancer, they can relieve symptoms and promote tissue repair by suppressing inflammation. However, in some diseases, excessive activation of M2 macrophages can also promote disease progression.
In recent years, the development of therapies targeting M2 macrophages has been advancing. For example, in cancer treatment, it is hoped that disease progression can be slowed by suppressing the action of M2 macrophages in helping the proliferation and metastasis of cancer cells. In addition, in chronic inflammatory diseases and autoimmune diseases, treatments that utilize the anti-inflammatory action of M2 macrophages are being considered.
What results were obtained?
The results of this paper suggested that exosomes (MSC-sEVs) released over time from mesenchymal stem/stromal cells (MSC) induce a series of cellular responses that lead to improved functional recovery in an experimental model of spinal cord injury (SCI). These exosomes were taken up by M2 macrophages, increasing the expression of transforming growth factor beta (TGF-β), followed by upregulation of TGF-β receptors and numerous proteins related to the function of the microvasculature surrounding the spinal cord injury, ultimately leading to functional stabilization of the spinal cord microvasculature. To obtain a therapeutic effect similar to a single injection of MSC, MSC-sEVs had to be administered in divided doses over three days. Intravenous injection of divided MSC-exosomes mimicked the effects of a single dose of MSC cells on multiple parameters, including increased expression of M2 macrophage markers, upregulation of TGF-β, TGF-β receptors, and proteins related to microvasculature function, and reduced permeability of the spinal cord microvasculature.
Reference; Damage to the microvasculature surrounding the spinal cord injury (the blood-spinal cord barrier) is thought to be related to secondary injury in spinal cord injury.
The red inverted triangles are the exosome divided-dose group. The blue circles are the MSC cell administration group, the green triangles are the single-dose exosome group, and the gray squares are rats that received no treatment. When administering the same amount of exosomes, the therapeutic effect was higher when administered divided over three days than as a single dose. Divided-dose administration of exosomes achieved the same effect as cell therapy. Because exosome therapy has higher safety and greater developmental potential than cell therapy, expectations are high for its future development.
What are the limitations of this study?
This study was conducted in rats, and it is unclear whether the results can be applied to humans. In addition, the mechanism underlying the therapeutic effect of MSC-exosomes has not been fully elucidated, and further investigation is needed. Specifically, the optimal dose and timing of MSC-exosome administration need to be determined. It is also necessary to evaluate the long-term effects and potential side effects of MSC-exosome treatment on SCI recovery. This study did not investigate the effects of MSC-exosomes on other cell types involved in spinal cord injury, such as oligodendrocytes and neurons.
What is the future of this study?
Improvements in the dose and method of administration of MSC-exosomes are needed. Further research will likely be needed to determine whether extending the treatment period through additional injections or osmotic pump delivery can further promote recovery. Further in vitro and in vivo studies will also be needed to understand how MSC exosomes affect macrophage function.
Impressions
MSC cell therapy has a long history, and much basic research has been conducted. Clinical application is also advancing. However, its therapeutic mechanism is not clear. In this paper, it was suggested that after the administered MSC cells are transplanted into the body, they may exert their therapeutic effect via exosomes. Furthermore, the fact that a similar therapeutic effect was obtained by intravenously injecting exosomes from outside suggests that MSC exosomes themselves contain something that exerts a therapeutic effect, and that exosomes themselves could become a new therapeutic drug. In the future, we await further research findings on what these exosomes contain and what kind of molecular changes they cause after being taken up by the macrophages present around the spinal cord injury site.