Stem Cell Therapy For Spinal Cord Injuries

Overview

Spinal cord injury (SCI) is a severe neurological condition characterised by complications in movement, sensory, and automatic body functions.¹ The main causes of SCI include road traffic accidents, falls, sports-related injuries, primarily diving, and other traumatic events. SCI occurs when the tissues that surround and protect the spinal cord, such as ligaments (connective tissues that hold bones together), muscles, and bones are damaged and unable to absorb the force from an injury. The severity of SCI is largely dependent on the intensity of the initial damage to the spinal cord. 

What are spinal cord injuries?

The spinal cord is a part of the body's central nervous system (CNS), extending from the brain to the lower back, and plays a crucial role in transmitting nerve signals throughout the body.⁵ 

Immediate consequences and symptoms of SCI include:^1,6

• Weakness in limbs
• Loss of feeling and movement below the point of injury (spinal shock)
• Abdominal breathing
• Low blood pressure (hypotension)
• Spinal cord pain or deformity
• Reduced bowel movement (constipation)
• Prolonged penile erection (priapism)
• Respiratory problems
• Skin complications

The diagnosis of SCI is primarily performed through a radiological examination of the entire spine. Computed tomography (CT) is commonly used due to its ability to visualise the spine in difficult-to-access regions with X-rays.¹ Magnetic resonance imaging (MRI), which uses a combination of magnetic fields and radio waves, can also be employed to further classify the injury. 

Damage from SCI comprises two different mechanisms.⁶ The first is primary damage which occurs immediately at the time of injury. The second is the secondary damage cascade that develops over hours to months. This cascade involves tissue swelling from internal bleeding (haemorrhage) and fluid retention (oedema), inflammation, and excessive scar formation (gliosis). As it is difficult to accomplish complete recovery from SCI, the current focus of SCI treatment is to mitigate the secondary damage cascade through neuroprotection, which can be categorised into three phases: acute (within a few days), sub-acute (a few days to 6 months), and chronic (over 6 months). 

Current treatments for SCI

Despite advancements in strategies to protect the nervous system from secondary damage, there is still no effective treatment for restoring lost function in the spinal cord after SCI.² This is because SCI leads to a range of cellular damage that changes with time, making it challenging for a single drug to effectively target and mitigate all the damage. 

Furthermore, the CNS has a limited ability to regenerate cells and restore neuronal connections due to:¹

• The complexity of neural networks
• The limited number of neural stem cells
• The formation of scar tissue that creates an inhibitory environment
• The body’s natural immune response which leads to inflammation 

Therefore, neuroprotection using immunosuppressants and rehabilitation forms the foundation of current SCI treatment.¹ In cases where these interventions are ineffective, surgical treatment may be considered. This typically involves decompression to increase the space for nerves to pass through and stabilisation to prevent future complications from fractured bones. 

Given these circumstances, stem cell therapies have garnered considerable interest, as they provide multiple avenues for promoting recovery and reducing SCI-related damage.

What is stem cell therapy?

Stem cells have the ability to replicate themselves, a process known as self-renewal, and to develop into different cell types, a process known as cellular differentiation.¹ Stem cells show great potential in treating SCI due to their capability to replace damaged cells and create a cellular environment that promotes recovery.⁴ 

Stem cells can be classified by their potency, which is the capacity of a cell to differentiate into other cell types. The more cell types a stem cell can differentiate into, the greater its potency. 

There are five different classes of stem cells:

• Totipotent stem cells - these cells can differentiate into any cell type
• Pluripotent stem cells - they can differentiate into any cell type in adults
• Multipotent stem cells  - they can differentiate into a specific range of cell types
• Oligopotent stem cells  - they can differentiate into a few cell types
• Unipotent stem cells can only differentiate into a single cell type

Stem cells used for therapy can be either autologous, meaning they are derived from the patient, or allogeneic, meaning they are obtained from a donor. Previous studies suggest that the mechanism by which stem cells treat SCI involves the cells migrating to the injury site, differentiating into specific cell types to replace damaged cells, and increasing the production of proteins that promote tissue repair.³ 

There are several different methods for introducing stem cells into a patient’s body, including delivery into the blood vessels (intravenous or intra-arterial), direct injection into the spinal cord (intrathecal or intralesional), and scaffold-based implants.^1,2,3 

Current research and clinical trials

Previous and current clinical trials primarily focus on assessing the safety and effectiveness of stem cell therapies.³ While most studies have reported no major safety concerns, the results regarding symptom improvement vary widely. 

The types of stem cells commonly used in clinical trials for stem cell therapy for SCI include:^1,2,3,4,6

• Neural stem cells (NSCs)
  • Multipotent and are the only adult stem cells capable of differentiating into the three main types of neural cells
  • Mostly found in the CNS of developing foetuses but also occur in limited regions in the adult brain
  • Stimulate tissue regeneration and support the formation of new connections in the injured spinal cord by promoting the development of neural cells and restoring missing neurons
  • A few studies employing NSCs have shown several surgery-related severe adverse events, but improvements range from significant to none at all
• Embryonic stem cells (ESCs)
  • Totipotent or pluripotent cells that can differentiate into many cell types 
  • Has to be harvested from embryos
  • Clinical trials have shown promising results in promoting tissue regeneration
• Mesenchymal stem cells (MSCs)
  • Multipotent cells that can differentiate into heart, muscle, skeleton and bone cells
  • Can be harvested from the bone marrow (a tissue found in the centre of bones), umbilical cord, or body fat (adipose tissue) 
  • No adverse symptoms have been associated with MSC-based treatments so far, but neurological improvement has been limited

Other cells that show potential in stem cell therapy, but have yet to show tangible results, include:^4,6

• Induced pluripotent stem cells (iPSCs)
  • Adult body cells that are reprogrammed back into a pluripotent state, resembling ESCs
  • The first human clinical trials began in 2021, but no results have been published yet ⁷
• Muse cells
  • Pluripotent stem cells are found in the bone marrow, blood, and connective tissues of organs 
  • Can accumulate at the site of injury after intravenous administration, eliminating the need for surgical procedures

A major challenge in SCI clinical trials is considering the various unique factors that could influence a patient's recovery trajectory.² The effectiveness of stem cell therapy depends on various factors, such as the method of administration (intravenous, intra-arterial, intrathecal, or intralesional), the number of cells administered, and the type of cells used. Therefore, further investigation is required to optimise treatment outcomes. 

Considerations in stem cell therapy

One of the greatest challenges in stem cell therapy is the risk of graft-vs-host disease, where the patient's immune system recognises the administered stem cells as foreign and attacks them.⁶ Autologous cells (derived from the patient) have a lower risk of rejection but are more cost-intensive.^2,6 In contrast, allogeneic cells (from a donor) are less expensive and suitable for large-scale production but carry a higher risk of rejection. However, autologous cells may be less effective due to the damaged environment, requiring a larger number of cells to achieve a therapeutic effect. 

To mitigate the risk of rejection with allogeneic cells, these cells can be genetically modified to reduce the likelihood of an immune response.² Alternatively, immunosuppressive drugs can be used, though they often have significant side effects and increase the risk of infections. Patient-derived iPSCs require less immunosuppression and avoid major ethical concerns, but they come with the added risk of potential tumour development.⁶

Future considerations

Given the inconsistencies in producing safe and effective results, researchers have emphasised the need for more randomised and controlled trials with larger patient cohorts to generate more reliable data.¹. However, challenges such as low patient recruitment, due to the low incidence of SCI, and limited funding remain significant obstacles. Researchers also argue that a holistic and personalised approach, rather than a one-size-fits-all strategy, is necessary to maximise the effectiveness of stem cell therapies in the diverse SCI patient population.²

Summary

The spinal cord is a crucial part of the body, and its injuries can have severe negative impacts on an individual's life. Spinal cord injuries (SCI) are two types: primary damage and secondary damage. Most current treatments focus on reducing further damage but are unable to repair the damage that has already occurred. These methods include neuroprotection with immunosuppressants, rehabilitation, and surgical intervention. Stem cell therapy, however, offers the potential to restore lost neurological function in the spinal cord.

Stem cells used for therapy can be either autologous (derived from the patient) or allogeneic (obtained from a donor). The stem cell types commonly used in current clinical trials include neural stem cells, embryonic stem cells, and mesenchymal stem cells. Additionally, induced pluripotent stem cells and mouse cells show great potential, although their effectiveness has yet to be fully studied. While clinical trial outcomes are promising, several factors still require further investigation before stem cell therapies can reach their full potential.