Stem cells: a cure for spinal cord injury

Diya Adhikary, Amity University Kolkata

The spinal cord, a long bundle of nerves and cells, extends from the end of the brain stem (medulla oblongata) to almost the bottom of the spine (lumbar region of the vertebral column). The body’s central supporting structure plays a vital role in conducting signals to and from the brain and also helps in maintaining an erect body posture. Spinal cord injury (abbreviated as SCI) is generally caused by extreme trauma, such as after road accidents, sudden shock due to falling from heights, acts of violence (gunshot or stab wound), etc. Non-traumatic SCI might be caused by cancer, spinal disk degeneration (also called degenerative disk disease/DDD), or arthritis, which lead to direct or indirect neural tissue damage. Damage of grey matter (also called gray matter) and white matter after SCI leads to partial or complete loss of function (motor, sensory or autonomic) in parts of the body distal to the lesion/injury site. Injury to the cervical spine with high-grade dysfunction of the CNS is the most devastating of all SCIs. In severe cases, the mortality risk is higher compared to the other diseases as the tissue repair becomes difficult due to loss of cells, axon regeneration failure, and time-sensitive pathophysiology. Patients not only suffer from physical and physiological harm but their families also suffer from a huge economic burden. 

CAUSES: 

• A traumatic spinal cord injury (a sudden traumatic blow) caused by an accident, gunshot, knife-stabbing, etc. can fracture, dislocate, crush or compress one or more vertebrae of the spinal cord. Additional damage to the spinal cord occurs due to bleeding, swelling, inflammation, and fluid accumulation in or around it. 
• A non-traumatic spinal cord injury can occur due to arthritis, cancer, inflammation, infections, or disk degeneration of the spine.

Whatever be the cause (traumatic or non-traumatic), damage of the spinal cord affects the nerve fibres passing through the injured region. This might lead to impairment of a part or all of its corresponding muscles and nerves present at or below the site of injury.

STEM CELLS:

Stem cells have the ability of self-renewal and totipotency. Due to their self-renewal ability, they can undergo asymmetric division into a stem cell (without signs of aging) and another daughter cell (restricted to one of the germ layers). It may become quiescent and at later stages re-enter the cell division cycle. As a stem cell is totipotent, it can become any cell type present in an organism. In simple words, it can be said that, in undergoing the asymmetric type of cell division (ACD), a stem cell produces a copy of itself (has differentiation potential) and another daughter cell (has the ability to enter the path of differentiation). Thus, the division into a stem cell and another daughter cell maintain a balance (or functional diversity) between the stem cell and progenitor cell pool in the body.

TYPES OF STEM CELLS USED IN TREATMENT:

The common stem cell types used for the treatment of spinal cord injury are:

• Mesenchymal Stem Cells (MSCs) — Bone marrow mesenchymal stem cells (BM-MSCs), human umbilical cord mesenchymal stem cells (HUC-MSCs) and adipose-derived mesenchymal stem cells (AD-MSCs) are some of the most commonly used MSCs in clinical practice.

1. BM-MSCs have a therapeutic effect on many diseases. The transplanted BM-MSCs can cross the blood-brain barrier without interfering with their structure. After transplantation, they can move to the injured region and differentiate into neurons or neuron-like cells. They exert neuroprotective effects by secreting various neurotrophic factors (NTFs). These factors are protein molecules that support the survival, development, and differentiation of neurons (both developing and mature). 
2. HUC-MSCs are also used to treat SCI in humans and animals. It has been reported by certain research studies that rat survivability and electrophysiological monitoring results were better when treated with HUC-MSCs, as compared to the application of BM-MSCs. Another study has experimentally found that this leads to the regeneration of damaged neurons and improvement of the sensory and motor functions after complete SCI.
3. AD-MSCs also have therapeutic effects in various diseases. A study showed that when AD-MSCs were injected in adult dogs suffering from acute SCI, it prevented further damage by enhancing antioxidant and anti-inflammatory mechanisms, moreover no adverse reactions were found. 

• Hematopoietic Stem Cells (HSCs) — In recent years, the focus has been on the use of HSCs to treat patients suffering from SCI. Certain studies have reported that experimental rat models showed significant recovery from neurological damages after being injected with HSCs.

• Neural Stem Cells (NSCs) — According to several studies, NSC transplantation promotes neurological function recovery after SCI. Though endogenous NSCs are normally silenced, they can be activated under a variety of pathological conditions. After activation, they migrate to the site of injury and support nerve repair. A neural cell-specific gene expression system can be used in combination with NSCs to treat SCI. Overexpression of granulocyte-macrophage colony-stimulating factor (GMCSF) in NSCs and exertion of neuroprotective effects can be induced by neuronal cell-specific gene expression systems. 

• Induced Pluripotent Stem Cells (iPSCs) — This is still in the experimental stage. iPSCs taken from 86-year-old healthy males were injected into immunodeficient rats after SCI. A certain study reported that iPSCs survived and differentiated into neurons and glial cells, they extended tens of thousands of axons from the injury site, thereby covering almost the entire rat CNS (central nervous system). It was concluded that iPSC transplantation can improve the recovery of motor function in SCI rats. However, it has a low survival rate and tumor formation possibility at the transplant site. Later, another study found that hydrogel injection caused the early survival of iPSC-derived oligodendrocytes and reduction of teratoma formation.

• Embryonic Stem Cells (ESCs) — ESCs, in vivo or in vitro, can be induced to differentiate into almost all cell types. This makes them one of the most promising stem cells for the treatment of SCI. Human embryonic cell-derived oligodendrocyte progenitor cells were injected into the injury site of nude mice. A study found that progenitor cells could migrate to the spinal cord and brain stem, thus decrease the parenchymal cavity of the injury site, thereby promoting axon survivability as well as improving motor function without causing adverse reactions such as pain, toxicity, tumor, etc.

• Other Stem Cells — According to recent studies, some other stem cells can also be used to cure SCI. The Dental Pulp Stem Cells (DPSCs) are potentially capable of differentiating into neural-like cells and myocyte-like cells. 

1. Injection of Dental Pulp Stem Cells (DPSCs) promotes axon regeneration and survival of endogenous neurons and glia within and around the lesion site (a paracrine-mediated mechanism).
2. Olfactory ensheathing cells (OECs) transplantation for SCI treatment has been gradually revealed over the past decades. Due to the feature of modulating the host environment to promote remyelination, it has emerged as a promising repair strategy. In addition, a study reported that OEC activation (adding neurotrophins) enhanced its therapeutic potential in spinal cord repair and improved neurological recovery. Olfactory bulb tissue could be stored before culture without any compromise in the viability of cells, due to which one can obtain a large number of cells for clinic use.

Mechanism of use of stem cell in curing spinal cord:

• Tissue repair and replacement: The process of SCI repair is initiated by translocated SCs. They could differentiate into neurons and glial cells (under stimulation of the internal environment and various nerve growth factors).
•  Neurotrophic and Regenerative effects: Nerve regeneration and neurotrophicity are the important factors in the process of SCI repair. Glial cell-derived neurotrophic factor (GDNF) plays a vital role in SCI repair and NSCs perform a crucial function in nerve regeneration and nutrition.
• Promotion of Angiogenesis: It is not only on the regeneration of nerve cells but also the support of the surrounding microenvironment (blood vessels and extracellular matrix) upon which the recovery of neurological function depends. Vascular regeneration is a valuable therapeutic research aspect. It can promote nerve repair and axonal regeneration thereby promoting the improvement of neurological function.
• Anti-apoptotic effect: This is closely related to the recovery of neurological diseases (SCI). A study found that stem cell transplantation can interfere with the balance between pro-apoptotic and anti-apoptotic factors thereby reducing early neuronal apoptosis. This contributes to the survival of tissues, motor neurons, and the recovery of neurological functions in the patient.
• Anti-Inflammatory effect: It is another important mechanism of stem cell transplantation for SCI treatment. Neural stem cells (NSC) conditioned medium could improve the neurological functions in SCI by inhibiting the inflammatory response, thus achieving the corresponding therapeutic effect. After SC transplantation, it exerts anti-inflammatory effects and cooperates with other related mechanisms thus promoting tissue function repair after SCI.

Potential:

Japan is the first country to have managed to receive government approval for carrying out Stem Cell Therapy in patients. Though a Japanese government organization in Kobe has been giving advice and support to the project for more than a decade, independent researchers state that the approval is based on a small and poorly designed clinical trial. It is difficult to state whether the treatment has long-term efficacy as it is hard to rule out if the patients recovered naturally. The Mesenchymal Stem Cells (MSCs) are thought to be safe but the infusion of stem cells into the blood causes dangerous blood clots in the lungs. Hence, there is still confusion about whether they actually benefit the cause. The team can market and sell the therapy as long as they collect data from the participants over the next seven years, as they have to show that it works but people can start paying for the treatment in the next few months. Still, some of the independent scientists think that in order to know if the treatment is actually working or not there should be a double-blind study.

Due to the lack of large-scale clinical studies, stem cell therapy for spinal cord injuries (SCI) needs to be conducted in animal models and then requires large-scale and multicenter clinical trials. Targeting Embryonic Stem Cells (ESCs) and the application of stem cells might be a promising aspect for SCI treatment in the future.

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Reference:

1. Gazdic, M., Volarevic, V., Harrell, C. R., Fellabaum, C., Jovicic, N., Arsenijevic, N., & Stojkovic, M. (2018). Stem Cells Therapy for Spinal Cord Injury. International journal of molecular sciences, 19(4), 1039. https://doi.org/10.3390/ijms19041039

2. Schroeder, G. D., Kepler, C. K., & Vaccaro, A. R. (2016). The Use of Cell Transplantation in Spinal Cord Injuries. The Journal of the American Academy of Orthopaedic Surgeons, 24(4), 266–275. https://doi.org/10.5435/JAAOS-D-14-00375

3. Scientists Repair Injured Spinal Cord Using Patients’ Own Stem Cells

DOI: https://neurosciencenews.com/sci-stem-cell-repair-17845/

4. Huang, L., Fu, C., Xiong, F., He, C., & Wei, Q. (2021). Stem Cell Therapy for Spinal Cord Injury. Cell transplantation, 30, 963689721989266. https://doi.org/10.1177/0963689721989266

5. Jana Vaskovic, Spinal Cord – Anatomy, structure, tracts and function. https://www.kenhub.com/en/library/anatomy/the-spinal-cord

6. Rachel Nall, A guide to the spinal cord: Anatomy and injuries. Medical News Today, 2019 November. https://www.medicalnewstoday.com/articles/326984

7. Spinal cord injury. https://www.mayoclinic.org/diseases-conditions/spinal-cord-injury/symptoms-causes/syc-20377890

8. Nandoe Tewarie, R. S., Hurtado, A., Bartels, R. H., Grotenhuis, A., & Oudega, M. (2009). Stem cell-based therapies for spinal cord injury. The journal of spinal cord medicine, 32(2), 105–114. https://doi.org/10.1080/10790268.2009.11760761

9. Gao, L., Peng, Y., Xu, W., He, P., Li, T., Lu, X., & Chen, G. (2020). Progress in Stem Cell Therapy for Spinal Cord Injury. Stem cells international, 2020, 2853650. https://doi.org/10.1155/2020/2853650

10. Spinal Cord Injury: Hope Through Research. National Institute of Neurological Disorders and Stroke, 2017 June. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/spinal-cord-injury-Hope-Through-Research

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