I am currently conducting a study to verify the therapeutic effects of extracellular vesicles (exosomes) derived from bone marrow mesenchymal stem cells (MSCs) and aiming for their clinical applications in various diseases. In our previous study using a rat spinal cord injury model, we reported the potential of exosomes to play a major role in the therapeutic mechanism of MSC intravenous therapy, indicating that MSCs may exert their therapeutic effects through exosomes.
However, our previous study focused on rat exosomes using rat MSCs, and there might be differences between rats and humans. In this study, we are validating the use of human MSC exosomes for clinical applications of exosome therapy, specifically targeting “spinal cord injury.”
The initial goal was to verify the improvement in paralysis, but during the ongoing observations, we noticed a significant difference in body size between the treatment group and the control group. In clinical settings, severely spinal cord injury patients tend to experience continuous weight loss during the acute phase. While the reduction in muscle mass due to paralysis plays a significant role, excessive muscle loss can diminish the effectiveness of rehabilitation.
The phenomena confirmed by human MSC exosome intravenous therapy are:
- Promotion of motor function recovery
- Immunomodulatory effects at the injury site
- Suppression of circulating inflammatory cytokine levels
- Inhibition of decreased growth hormone receptor in the liver
- Increase of Insulin-like growth factor-1 (IGF-1), an important cytokine in body growth, circulating throughout the body
Let’s now take a closer look at the actual content of the research paper.
What is Spinal Cord Injury?
Spinal cord injury occurs when the spinal cord is physically damaged. It is often caused by various accidents such as traffic accidents, sports accidents, and falls. Spinal cord injury has the potential to cause the loss of sensation and motor function, and in severe cases, it can lead to quadriplegia (a state of losing all or part of the sensation and motor function in the limbs). Currently, there are limited effective drugs and treatments to improve this paralysis at the medical level, and their effectiveness is insufficient, leaving many patients to live with disabilities.
Spinal Cord Injury and Body Growth
Spinal cord injury not only causes severe sensory and motor impairments in young adults but also delays growth during the acute to subacute phases. Inflammatory cytokines circulating throughout the body are associated with growth impairment and muscle wasting. However, recent studies have suggested that small extracellular vesicles (sEVs) derived from human mesenchymal stem cells (MSCs) have therapeutic effects on growth and motor recovery after severe spinal cord injury in young adult rats, potentially regulating inflammatory cytokines.
What are MSC-Derived sEVs?
Mesenchymal stem cells (MSCs) are specialized cells found in various locations within the body, such as bone marrow and adipose tissue. These cells possess self-repair and immune-regulating abilities. Small extracellular vesicles (sEVs) secreted by MSCs facilitate intercellular communication and have the ability to regulate inflammatory responses. Among MSCs, bone marrow-derived MSCs are the most extensively studied and clinically researched stem cells.
Research Methodology
In this study, rats with spinal cord injuries were randomly assigned to three different treatment groups: human and rat MSC-sEVs groups, and PBS group (control). Treatment was administered on the 7th day after spinal cord injury. The recovery of motor function and body growth was evaluated weekly until the 70th day post-injury. The movement of sEVs within the body, uptake of sEVs by cells, expression of macrophage phenotypes at the injury site, as well as cytokine levels in the injury site, liver, and circulating throughout the body were also evaluated.
Research Results
The results of the study demonstrated that intravenous administration of both human and rat MSC-sEVs improved the recovery of motor function and restored normal body growth in young adult rats with spinal cord injury.
BBB Score: 21 out of 21 points. 0 indicates complete paralysis, while 21 indicates no paralysis. The exosome treatment group showed significantly better motor function recovery.
The control group rats with spinal cord injuries appear emaciated (B), while the exosome treatment group (C: human exosomes, D: rat exosomes)
When human exosomes were administered intravenously, they were selectively taken up by macrophages/microglia at the lesion site.
In vitro experiments revealed that they were specifically taken up by activated M2 macrophages in an environment with pH 6.
Furthermore, the administration of human or rat MSC-sEVs increased the proportion of M2 macrophages and reduced the production of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, which are pro-inflammatory cytokines, at the injury site.
In addition, the levels of circulating TNF-α and IL-6 in the serum decreased, while the production levels of growth hormone receptor (GHR) and IGF-1 in the liver increased. Moreover, a significant increase in serum IGF-1 levels was confirmed in the treatment group.
IGF-1 stands for Insulin-like Growth Factor 1, which is a hormone produced in the human body. This hormone assists the action of growth hormone (GH) and plays an important role in body growth and development.
IGF-1 particularly promotes the growth of bones and muscles. It also stimulates cell growth and differentiation, aiding in the generation of new cells for body repair and regeneration. Furthermore, IGF-1 is involved in regulating blood glucose levels.
However, improper levels of IGF-1 can lead to issues in body growth and development. For example, low levels of IGF-1 may result in delayed growth, while excessively high levels of IGF-1 can cause excessive growth and other health problems.
Conclusion
The results of this study suggest that intravenous MSC-sEV therapy contributes to the recovery of body growth in young adult rats with spinal cord injury by reducing systemic pro-inflammatory cytokines and increasing GHR and IGF-1 production in the liver. Human-derived MSC-sEVs had similar effects as rat-derived MSC-sEVs, promoting both functional recovery and normalization of body growth. These findings indicate the potential alleviation of growth interruption after spinal cord injury in young rats through hMSC-sEV therapy. These results have important therapeutic implications for spinal cord injury patients, particularly young individuals who may experience growth interruption as a significant concern.
