Due to the central nervous system’s (CNS) limited capacity for regeneration, neurological deficits are typically irreversible. In addition, neurological diseases have a limited range of therapeutic options.

Recently, mesenchymal stem cell (MSC) therapy has given many patients hope. MSCs have shown three remarkable mechanisms of action to treat neurodegenerative illnesses: homing to damaged brain areas, secreting paracrine neuroprotective substances, and controlling immune cell activity. These capacities of MSCs allow damaged neural tissue to regenerate. Therefore, various clinical trials have been investigated based on MSCs’ regeneration capacity, and several have shown tremendous promise. These include the most prevalent diseases, such as stroke, traumatic brain injury, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, multiple sclerosis, and spinal cord injury.

MSCs’ Potential in Stroke Therapy

Stroke causes abrupt neurological impairments that result from a disturbance in the cortical circulatory system. Due to their potential for neuroprotection, neurogenesis, and immunomodulation, MSCs have undergone substantial research as a potential treatment in numerous trials in acute or chronic stages. In addition to neuronal loss, the inflammatory response is enhanced in acute stroke, which results in the destruction of hypoxic tissue in the region of the injury zone and the start of cytokine cascades that enlarge the damaged area. However, inflammation is decreased by MSCs’ capacity to transport immunomodulatory and neuroprotective factors. In addition, administration of MSCs during the chronic stage of stroke has been demonstrated to activate regenerative mechanisms that may aid in restoring brain function.

MSCs’ Potential in Traumatic Brain Injury Therapy

The most severe disease, traumatic brain injury (TBI), can cause death or serious damage to neurological processes. TBI harm can be broken down into two phases. The early stage is the direct result of the initial insult, resulting in blood-brain barrier (BBB) rupture, brain oedema, and cranial bleeding, which causes fast cell death in the affected brain area. The following stage is associated with the release of excitatory amino acids, ionic imbalance, calcium overload, mitochondrial malfunction, and continuing neurodegeneration. Additionally, immune and inflammatory reactions that follow brain injury increase neuronal death.

Following the release of pro-inflammatory cytokines, the migration of immune cells, and the activation of microglia, post-traumatic neuroinflammation develops. The previous studies demonstrated that TBI-induced motor and cognitive deficits in mice were mitigated by administering MSCs directly into the injured brain. Moreover, administering MSC therapy to TBI animals stimulated the damaged brain to produce trophic factors that reduce inflammation, support neurogenesis, neuroprotection, and neural regeneration. 

MSCs’ Potential in Alzheimer’s Disease Therapy

Alzheimer’s disease (AD) is a prevalent neurodegenerative condition that can be identified by a decline in cognition, memory loss, disruptive behaviours, and aphasia. The pathogenic alterations of AD include aberrant amyloid β-protein (Aβ) accumulation and abnormal tau protein phosphorylation, which result in neuroinflammation that damaging to the central nervous system. Interestingly, MSC infusion helps AD patients with their cognitive deficits by lowering A deposition and rescuing memory problems. In an AD mouse model, human MSCs have been found to reduce A levels via promoting autophagy of damaged neurons. These results might be accompanied by upregulation of the levels of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF), which could protect neurons and neuronal integrity in patients that receive MSC transplantation.

MSCs’ Potential in Huntington’s Disease Therapy

Huntington’s disease (HD) is caused by a mutation in the gene that codes for the huntingtin protein, which builds up excessively and is harmful to neural tissue in the stratum structure. Intriguingly, MSC-treated HD mice had reduced motor impairments and enhanced spatial memory. This effect is due to MSC providing trophic support with elevated BDNF levels in the striatum region of the brain, which stimulates endogenous neural stem cell growth. Moreover, the genetically modified MSCs overexpressing BDNF or NGF factors showed reduced apoptosis in the striatal area and reduced brain atrophy. Additionally, HD animals treated with MSCs have a longer lifespan than HD mice due to a decrease in misfolded huntingtin protein aggregates after MSC transplantation. Due to HD’s complicated manifestations, clinical therapy has been extremely difficult. So, the transplant of genetically engineered MSCs that are overexpressing BDNF was recommended as a clinical study in HD patients.

MSCs’ Potential in Parkinson’s Disease Therapy

Parkinson’s disease (PD) is a prevalent neurological condition that affects elderly people and is characterized by tremors, myotonia, and limited movement. The substantia nigra and striatum contain most of the lesions in PD. Reduced levels of dopamine (DA) are the result of PD, which leads to dopaminergic neuron degeneration. Interestingly, MSC transplantation has been proven to ameliorate PD-related poor motor functioning, decrease uncoordinated limb movement, enhance neurogenesis, stimulate neuroblast migration, and enhance locomotor activity. Moreover, MSCs contribute to cell replacement, anti-inflammatory therapy, and immune system regulation. Therefore, it appears that using MSCs with a high propensity for differentiation into DA cells is an effective technique in PD cell therapy.

MSCs’ Potential in Amyotrophic Lateral Sclerosis Therapy

Amyotrophic lateral sclerosis (ALS) is a complicated, progressive neurodegenerative disease that affects motor neurons. Its progression is linked to a number of pathogenic mechanisms, including mitochondrial failure, oxidative stress, and axonal destruction. In MSC transplantation, the cells can migrate to the spinal cord and reduce tissue glial proliferation and activation, which boosts the number of motor neurons, suggesting that MSCs may have neuroprotective properties from neurotrophic factors (NTFs). As a result of previous studies, NTFs are essential for the survival of neurons, stem cell treatment based on NTFs secreted by MSCs has shown promising results in clinical studies of ALS patients. According to this study, MSC-NTFs may increase the motor neurons’ duration of survival in ALS patients.

NTFs could be injected into the diseased neurons to halt the progression of the illness and increase ALS patients’ chances of surviving. Although there has been evidence of this therapy’s favourable safety and toleration, more clinical trials and academic studies are required to refine the therapeutic regimen and produce the greatest results.

MSCs’ Potential in Multiple Sclerosis Therapy

Multiple sclerosis (MS) is an autoimmune inflammatory disease that affects the central nervous system (CNS) when the immune system assaults its tissue, causing multifocal degenerative changes that are apparent as MS regions of demyelination and significant neuronal loss. There have been a number of clinical trials employing MSC transplantation for MS. MSCs’ anti-inflammatory properties help to protect neurons, decrease axon loss, and lessen neuronal necrosis and apoptosis in the brain and spinal cord. Moreover, the levels of trophic factors including interferon γ (IFN-γ) and HGF as well as anti-inflammatory cytokines like IL-4 and IL-10 increased in the peripheral blood of MS patients, confirming the immunomodulatory action of MSCs, which indicates a favourable clinical outcome. 

MSCs’ Potential in Spinal Cord Injury Therapy

Spinal cord injury (SCI) causes the neural motor and sensory circuit to be disrupted, which results in permanent impairment of the neural circuit. In a spinal cord injury, there are two pathological changes. Axons and blood vessels are disrupted as the main pathological changes following spinal injury. However, secondary alterations such as altered local ionic concentrations, loss of blood pressure control, decreased blood flow through the spinal cord, disruption of the BBB, immune response activation, cell apoptosis, and excitotoxicity cause patients to deteriorate and harm the regeneration process.

As a result, stem cell transplant therapy might help in inhibiting these processes. The clinical data has shown that there was a decrease in fibrosis and a post-injury lesion as well as an increase in angiogenesis, oligodendrocyte proliferation, axonal regeneration, and re-myelination after MSC transplantation in SCI patients.

Other than having a therapeutic effect on the listed neurological diseases, MSCs have also shown potential as a drug delivery vehicle for brain tumours. The initial clinical trials of MSC transplantation for CNS diseases and experimental research utilizing animal models collectively show that these cells have beneficial therapeutic benefits. This is because MSCs have a number of benefits, including an increase in cell survival and proliferation, neuroprotection and regeneration, immunomodulation, and a delay in the progression of the disease. Clinical investigations have revealed beneficial outcomes such as safety, tolerability, and functional improvements following the transplantation of MSCs, even though some results are not fully optimized. However, additional research may help to improve methods for obtaining greater numbers of healthy cells for use in cell treatments and to lessen the diversity of outcomes caused by the biological properties of MSCs.

References

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2. Soares MBP, Gonçalves RGJ, Vasques JF, da Silva-Junior AJ, Gubert F, Santos GC, de Santana TA, Almeida Sampaio GL, Silva DN, Dominici M, Mendez-Otero R. Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases. Front Mol Neurosci. 2022; 15: 883378.
3. Yao P, Zhou L, Zhu L, Zhou B, Yu Q. Mesenchymal Stem Cells: A Potential Therapeutic Strategy for Neurodegenerative Diseases. Eur Neurol. 2020; 83(3): 235-241.