Stem Cell Therapy for Traumatic Brain Injury

What is Traumatic Brain Injury? 

Traumatic brain injury (TBI) is a major cause of injury related death and disabilities in the USA and worldwide. According to the CDC, 30% of all injury related deaths (153 people per day in the USA) are attributable to TBI. Cognitive deficits, impaired memory, movement disorders, loss of hearing and vision, and psychological problems are common among the survivors.

What are Common Symptoms?

Traumatic brain injury can have wide-ranging physical and psychological effects. Some signs or symptoms may appear immediately after the traumatic event, while others may appear days or weeks later. The symptoms can vary depending on the severity of the injury. 

Mild TBI

Physical symptoms: 

• Headache, nausea, vomiting, fatigue or drowsiness, speech problems, dizziness. 

Sensory symptoms:

• Blurred vision, ringing in the ears, changes in the ability to smell, sensitivity to light or sound. 

Cognitive, behavioral or mental symptoms:

• Loss of consciousness for seconds to minutes, confusion, disorientation, memory or concentration problems, mood changes, difficulty sleeping. 

Moderate to Severe TBI

It can include any of the signs and symptoms of mild injury,, as well as some other that can appear within the first hours to days after the head injury: 

Physical symptoms: 

• Loss of consciousness from several minutes to hours, persistent headache, repeated vomiting or nausea, convulsions or seizures, dilation of one or both pupils, clear fluids draining from the nose or ears, inability to awaken from sleep, weakness or numbness in finger and toes.

Cognitive or mental symptoms: 

• Profound confusion, agitation, slurred speech, coma and other disorders of consciousness. 

Complications from a TBI

Several complications can occur immediately or soon after a TBI. Severe injuries increase the risk of a greater number of and more-severe complications. 

Moderate to severe TBI can result in prolonged or permanent changes in a person’s state of consciousness, awareness or responsiveness, which can vary from a coma and minimally conscious state, to a vegetative state and brain death. 

Other physical complications can happen from weeks to months after the TBI. When they last for an extended period of time, they are referred to as persistent post-concussive symptoms. Some of them include: seizures, hydrocephalus (fluid buildup in the brain), infections, chronic headaches and vertigo.

Many people can also experience changes in their thinking (cognitive) skills. It may be more difficult to focus and take longer to process their thoughts. Some may also have communication and language problems following a TBI.

Other complications can include behavioral changes, emotional problems and sensory problems.

Current Treatment Options

The primary injury damages the blood-brain barrier (BBB) and destroys or damages the neuronal and glial tissues and causes secondary neurodegeneration. 

Treatment options include immediate emergency care, medication management and surgery when needed. After the acute phase other treatments include rehabilitation programs with physiatrist, occupational therapist, physical therapist, speech and language therapist, social workers and nurses, depending on the complications that the patient developed. 

Use of Mesenchymal Stem Cells 

Different clinical trials of drugs like erythropoietin and progesterone have failed to improve brain damage in human patients despite these having neuroprotective effects. Treatment with Mesenchymal Stem Cells (MSCs) is one of the promising approaches in regenerative therapy. 

Results of preclinical research have shown that transplantation of MSCs reduced secondary neurodegeneration and neuroinflammation, promoted neurogenesis and angiogenesis, and improved functional outcome in the experimental animals.

Delivery of MSCs to the brain

There are different delivery methods that continue under investigation, including intravenous infusion, intrathecal application and intranasal application. The only noninvasive route of MSC administration is the intranasal (i.n.) route. Transplanted cells move through the nasal mucosa and either penetrate the cribriform plate and take the olfactory pathway to the brain. They can also be injected because they can be distributed systemically.  

Time of delivery 

Delivering MSCs at an optimum time is also important for efficient therapeutic effect. Studies have shown a higher engraftment rate if they are transplanted soon after the onset of injury. The efficacy of the treatment is increased when it is implemented at an earlier time point. 

A study showed that the efficacy of the stem cells transplanted with an oral NSAID (celecoxib) increases the engraftment and differentiation of Stem Cells leading to enhanced wound tissue repair. 

Mechanism of action of the cells

Some of the characteristics and mechanisms by which Stem cells can be beneficial to TBI are: 

• Differentiation. Some studies have shown that MSC can differentiate neuronal and glial cells (these cells surround neurons and hold them in place, they also supply nutrients and oxygen to neurons and can destroy pathogens and remove dead neurons).
• Paracrine mechanism. MSCs can overcome the human leukocyte antigen barrier because of one of their characteristics: being immune-privileged (they can evade the immune system). A way the MCSs help repair injured tissues is by secretion of factors that help the brain tissues surrounding the injury to protect the uninjured cells. This promotes the survival and proliferation of existing cells or induce the neighboring cells to secrete molecules that help the survival and proliferation of the injured cells.
• Immunomodulatory effects.  MSCs can suppress the proliferation of T cells, inhibit the production of TNF (a proinflammatory cytokine) and increase the production of IL-10 (an antiinflammatory cytokine), suppressing the immune response and thereby promoting growth of healthy tissues.
• Angiogenic and anti-apoptotic effects. Stem cells create a microenvironment that helps in modulating the angiogenic deficit due to the injury, by secreting proangiogenic growth factors. They can also inhibit apoptosis and increase the survival of viable neurons. 

Functional recovery after the treatment

Motor deficiency, cognitive deficiency, depression, and anxiety-related disorders are the common after-effects of TBI. Several studies have shown the recovery of motor and cognitive deficiencies following the MSC therapy after TBI in experimental animals. 

Recent research indicates that exosomes that are released from MSCs may play a vital role in the therapeutic efficacy of the treatment. Exosomes are nano-sized vesicles that help in intracellular communication, they can transfer proteins, RNAs, miRNAs to other cells. There is some evidence that MSC-derived exosomes may have therapeutic effects equivalent to MSC after brain injury.

Although the majority of the trials have been conducted in animal models, the results of them have been promising and could become an incredible treatment for patients that normally don’t have many treatment options and that don’t have a significant improvement. 

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Source:

Das M, Mayilsamy K, Mohapatra SS, Mohapatra S. Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects. Rev Neurosci. 2019 Nov 26;30(8):839-855. 

https://www.mayoclinic.org/diseases-conditions/traumatic-brain-injury/symptoms-causes/syc-20378557

Image from: 

https://www.hopkinsmedicine.org/health/conditions-and-diseases/traumatic-brain-injury