Introduction

Neurodegenerative diseases are defined as chronic and acute conditions that target different areas of the central nervous system (CNS) causing loss of neural and glial cells in the brain and spinal cord (Tanna. T, Sachan. V, 2014). There are numerous types of these conditions each affecting different areas of the CNS making looking for treatment for these conditions difficult. These conditions take an ever-increasing toll on the global population due to how hard they are to treat and how severe they can be on the people who suffer from them. There are currently different theories on how to either treat or prevent them but overall, it seems that most of these conditions cannot be properly treated only alleviated to some degree. At this point in time one of the largest areas of medical research is looking into treatments for these devastating conditions.

Through animal models it has been seen that stem cell treatments are promising alternatives to traditional treatments to age related diseases such as osteoporosis and diabetes (Jiang. B, et al, 2024). Stem cells were first discovered in the early 1960s and have been defined as cells capable of self-renewal and the ability to differentiate into other types of cells. They can be classified as:

• Totipotent

• Pluripotent

• Multipotent

Adult stem cells are defined as multipotent and can be extracted from multiple areas of the body. These are endogenous adult stem cells; their key benefit is their use in autologous therapies where stem cells are extracted from the same patient thus avoiding ethical concerns. They are however limited in the range of cells they can differentiate into thus restricting uses, though inducing pluripotency can get around much of this. The discovery of neural stem cells (NSCs) nullified the previous belief that CNS was not capable of neurogenesis. It in fact continues throughout life through NSCs found in the hippocampal dentate gyrus. Many studies show transplantation of NSCs causes improved cognition in rat models showing their potential (Dantuma. E, et al, 2010). Mesenchymal stem cells (MSCs) are defined as cell populations which mostly comprise of stromal cells that show secretory immunomodulatory and homing properties. They are capable of self-renewal and can differentiate into a range of cells and express a lack of specific CD markers. They can be harvested from numerous sources including bone marrow, perinatal tissue and adipose tissue (Mehta. K. J, 2025).

Neural stem cells and their progeny termed neural precursor cells (NPC) are found in delineated niches in the CNS, they are self-renewing and can differentiate into different cell types in the brain. Electrical stimulation to NPCs is currently a compelling idea for treatment because of spatial and temporal precision that they afford, particularly when applied invasively. Electric fields are present endogenously and are important during development and wound healing. These endogenous fields have been observed to influence NPC behaviour within a mature CNS such their migration. Naturally after an injury NPCs can be activated meaning an increase in NSC proliferation, survival, migration and neurogenesis to aid in recovery albeit in a limited capacity. Development of digital health technologies such as wearable devices will lead to greater ease of recording patient data when receiving electrostimulation treatment. This could help in recording vital data and identify functional and sensitive biomarkers which will help optimise stimulation parameters of the therapy. Though this kind of treatment will require experts from multiple fields such as medical and engineering to help with manufacturing (Iwasa. S. N, et al, 2024).

Spinal cord injuries

One large area of struggle in medical research is the treatment of injuries to the spinal cord, ways of which to repair or reverse damage to are highly underdeveloped. One suggested method is through spinal cord regenerative therapy methods utilizing MSCs. MSCs proliferation abilities alongside their ability to release chemical factors that influence cell interactions within the spinal cord are useful in treating SCIs. Some of these factors include cytokines, exosomes with anti-inflammatory agents, vascular epithelial growth factors, nerve growth factors and brain derived neurotrophic factors. This not only allows faster nerve cell regeneration but also eliminates the effects of glial scarring. Another area regarding VEGF is that it works as an angiogenic factor which promotes pericyte recruitment to allow vascular tissue to mature and regenerate. This in the CNS neurons and blood vessels work in units called neurovascular units which allow VEGF to promote neuronal regeneration by enhancing nutrient flow. In practise there are several factors to address regarding introduction and transplantation of MSCs to trauma sites. This includes mode of transplantation, dose, frequency of MSCs, timing and type of SCI the patient has suffered all of which can complicate this process and must be addressed. One way to help is alterations within oxygen level during MSC transplantation, such as hypoxic treatment followed by reoxygenation. This seems to improve proliferative abilities and migratory factors of MSCs allowing them to regenerate numbers and relocate to affected areas as well as enhance their survival rate (Kennedy. H, 2024).

Traumatic brain injury

Traumatic brain injury (TBI) affects an estimated 10 million people world wide which results in things like death, severe long-term headaches, depression and an increased risk of Alzheimer’s disease and dementia. MSCs being multipotent stromal cells that can be extracted from almost any adult tissue with a wide range of potential cell types including osteogenic, adipogenic and chondrogenic lineages. MSCs require expression of certain antigens and lack of expression of others to ensure distinction from other cells that would be present in culture. Their ability to differentiate into neural cells alongside their ability home in on sites of injury and get through the blood brain barrier (BBB) makes them a good candidate for therapeutic studies for TBIs. Several mechanisms have been put forward to explain why MSCs will migrate to sites of TBI such as influence of chemokines and growth factors. Another hypothesis ifs adhesion of MSCs to the endothelium of injured tissues due to the expression of vascular cell adhesion molecule (VCAM-1). Studies have observed migration of MSCs towards injured lung cells suspensions which did not occur when MSCs were cocultured with healthy lung cells. This alongside a study which showed colonisation sites of MSCs around injured myocardial tissue in rat models but none in non-injured tissue. This all implies that MSCs can locate injured tissue and move around uninjured. MSCs may help influence NSCs or help indirectly by activating surrounding astrocytes alongside decreased expression of inflammation associated cytokines to help with repair of injured tissues. This could also aid in upregulating expression of TIMP3 gene in TBI animal models and help restore the blood brain barrier (Hasan. A, et al, 2017, Mehta. K. J, 2025).

MSCs could also be modified to produce soluble growth factors to enhance the survival of stem and neural cells in patients. These factors can be observed to promote angiogenesis and neurogenesis in injured brains, enhancing multiplication of neuronal cells at damaged sites. A study by Cox in 2011 looked into 10 children who had suffered TBI, they were implanted with MSCs, initially they had a Glasgow coma scale (GCS) between 5 and 8. Over the course of 6 months 7 of the children displayed improved GCS scores while the remaining 3 remained the same. During the study none of the children died or displayed adverse side effects. One drawback observed in using MSCs is the potential for patient’s anti-tumour response mechanisms to be suppressed by presence of stem cells (Hasan. A, et al, 2017). Despite great advances in nerve transplantation microsurgery and acute

neurological care improving neurological damage the global burden of these conditions remains high.

One point of favour of MSCs is that they will not normally elicit host rejection responses after transplantation highlighting their potential for regenerative therapies with clinical trials report low incidences of adverse effects. A paper in 2024 surveyed ongoing trials (at the time of its publication) od MSCs of TBI, TSCI and PNI and found none of them had progressed to phase 3 studies. As of 2024 most studies used MSCs derived from bone marrow, adipose tissue, umbilical cord pulp, dental pulp or Wharton’s jelly. Other sources of MSCs include amniotic tissue peripheral blood, skeletal muscle, testis, ovaries, hair follicles, skin and synovial tissues though no studies have used these for TBI despite animal studies implying they are suitable. One thing to consider is donor age when using BM-MSC due to donor age reducing long term viability in cell culture. As well as BM-MSCs being reported to be more susceptible to nutrient conditions than say AT-MSCs, the collection of BM also requires an invasive procedure. And the age of the donor can affect proliferation rate and differentiation rate of BM-MSCs. Outside of BM many sources of MSCs can be obtained more easily from the after effects of procedures such as liposuction or molar extraction which would otherwise be discarded as medical waste. As of 2024 152 studies have been registered for using MSC based therapies for neurological pathologies. IV administration of MSCs is currently the main way of inserting MSCs into patients with one drawback being accumulation of MSCs in the lungs. intrathecal, intranasal and intracranial administration may present way to circumvent this issue. There is overall still many challenges that need to be overcome before MSC treatments can be a viable for patients suffering with severe neurological injuries (Wang. X, et al, 2024).

Treating dementia

It is thought that around 50 million people live with some form of dementia with an estimated global cost of care being around 818 billion USD. With age being seen as a predominant risk factor that figure is set to rise 132 million people by 2050. Dementia is characterised by amnesia, progressive cognitive impairment, behavioural disturbance, disorientation and loss of daily function. Alzheimer’s disease is the most common associated pathology, 5% of which are familial. One approach is to use stem cells to upregulate resident NSC niches in an adult brain to stimulate hippocampal neurogenesis to help compensate for neurodegeneration. Due to its role in learning and memory which could help counter amnesic symptoms of early dementia. This could be done by introducing growth factors connected to neurogenesis such as BDNF, IGF+1, NGF and VEGF. The downside to this is hippocampal neurogenesis steadily decreases with age and one of the main targets of dementia, CA1 neurons are not helped by this treatment (Duncan. T, Valenzuela. M, 2017).

Exogenous cell therapies aim to restore degenerate neural networks and restore cognitive functions. In this method stem cells act as a cellular delivery system utilising a paracrine bystander mechanism through induced production of neuroprotective growth factors. This is a finely balanced, complex and multi-step process with each type of stem cell having different properties to achieve this approach. MSCs due to their accessibility and broad range of differentiation makes MSCs the most studied stem cell type. Through neuroreplacement by MSCs remains relatively limited due to low rates of neuronal differentiation and propensity for glial cell formation. Intravenously administered MSCs are also capable of crossing the BBB and effectively migrating to regions of neural injury without tumour genic and immune responses. This minimally invasive procedure has a significant advantage over traditional intracranial injection. IPSCs derived neurons are structurally and functionally mature and capable of forming electro physiologically active synaptic networks. Using transcription factors during induction process makes it possible for direct differentiation into specific neuronal subtypes such as dopaminergic neurons (Duncan. T, Valenzuela. M, 2017).

Treating Alzheimer’s disease

Alzheimer’s disease (AD) is an irreversible and progressive disorder which manifests as memory impairment, cognitive decline and dementia. Different regions of the brain are affected suffering synaptic loss, neurofibrillary tangles, deposits of plaque and loss of different types of neuronal cells. Some of the most common risk factors associated with AD include age, cardiovascular disease, low education and depression. ad MScs on intracerebral transplantation in mouse models have been shown to significantly reduce Abeta deposition levels and induce higher activation of microglia. This significantly restores memory and cognitive function. Another study showed they could also improve learning memory and neuropathology by up regulating IL-10 and vascular endothelial growth factor. Human uc-MSCs have exhibited similar effects on transplantation especially modulation of neuroinflammation. Studies showed that they can be induced to differentiate into choline acetyltransferase, which could be used for further transplantation. They could also be used to mediate neuroprotection by regulating neuronal death, neurogenesis and glial cell activation in the hippocampus and altering cytokine expression improving cognitive impairment (Tanna. T, Sachan. V, 2014, Duncan. T, Valenzuela. M, 2017).

A study by Blurton-jones in which NSCs were injected into hippocampal region of a transgenic AD mouse model which showed improved cognitive function despite no change in existing Abeta plagues or neurofibrillary tangles. This led to the discovery of brain derived neurotrophic factors which are important for neuron outgrowth and synapse formation which leads to improved cognition through increased synaptic density. The presence of amyloid precursor proteins (APP) particularly in high concentrations may reduce NSCs increasing risk of AD developing. Though it can also increase the level of glial differentiation of stem cells upon their transplantation reducing the efficiency of these therapies to improve cognition. Thus, levels of APP may need to be reduced in patients before treatment can begin. Similar studies also used Embryonic stem cells and IPSCs to obtain similar results. ESCs once transplanted into rodent models are shown to restore cognitive function after AD but this is limited due to their pluripotent nature. Transplantation of undifferentiated ESCs present risk uncontrolled cell growth and tumour development. However, pre-differentiation them into NSCs in vitro may circumvent this though they will predominantly generate cholinergic neurons (Dantuma. E, et al, 2010, Duncan. T, Valenzuela. M, 2017).

Use of stem cells to treat strokes

Ischemic strokes are characterised by an acute loss of neurons, astroglia and oligodendroglia cells and disruption of synaptic architecture due to cerebral artery occlusion. Due to unlimited self-renewal and their ease of differentiation ESCs have been proposed as an ideal source of treatment for neural disorders. One study showed ESCs transplanted into a rat cortex with severe ischemia, repaired neural tissue was found in lesion cavity as well as improved structural repair. Intracerebral transplantation of mouse ESCs could also be seen to improve motor and sensory function of stroke affected rats. One disadvantage of using ESCs are potential malignant transformations and teratoma formations (Hao. L, et al, 2014). Strokes in elderly people are a large concern due to leading to severe disability or death leading to a need for fast medical intervention and comprehensive rehabilitation. Though in the elderly there can be complications such as preexisting health conditions, reduced recovery capacity and mobility issues. A study in 2024 reported a novel approach to stroke treatment involving mitochondria derived from healthy MSCs to protect neurons in mice effected by ischemic strokes. This implies MSC-derived mitochondria could hold potential as a treatment for ischemic strokes. As well as provide insights into

new resources such as organelles between stem cells and EVs (Jiang. B, et al, 2024).

Another stem cell treatment proposed is using IPSCs reprogramed from somatic cells with defined factors opposed to using ESCs for treating strokes. One study showed IPSCs induced from mouse embryonic or adult fibroblasts by introducing certain factors can exhibit morphology and growth properties of ESCs and express marker genes. One drawback is that IPSCs were shown to trigger immune rejection in subjects. Increased concentration of some cytokines such as brain derived neurotrophic factors (BDNF) and VEGF in local areas either by gene modification or direct injector will dramatically promote migration of endogenous NSPCs to injured brain areas (Hao. L, et al, 2014).

Mesenchymal stem cells can be isolated from almost any tissue in mammals and their ability for self-renewal and differentiation into neural cells in vitro. This has proven by neuronal markers such as NeuN and their migration towards sources of lesions in the brain, this coupled with their non ethical and tissue rejection related concerns makes them a promising therapeutic approach to stroke treatments. Though these cell types measures will need to be further developed to improve cell tracking once inserted into the body ensuring they go to areas of stroke damage without entering other parts of the body. As well as other issues such as dosing, timing of treatment and other side effect monitoring (Hao. L, et al, 2014).

Treating Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant genetic disorder with its characteristics being choreic movements, dystonia, cognitive decline in coordination and behavioural difficulties. It is caused by a genetic mutation in the IT15 (Huntington) gene, expansion of the stretch CAG triplet repeats leading to variants in the Huntington’s proteins leading to eventual neuronal loss. Transplantation of human MSCs into HD mouse models show reduced striatal atrophy and induces functional recovery. They have also been shown to delay striatal decline in the mouse models and also provide long term behavioural benefits by triggering weak immune responses. Human trials show through intracerebral implantation improves cortical metabolism were observed. Knock out therapies could knock down mutant Huntington genes in HD effected neurons by genetically

engineered MSC transduced with lentivirus to express siRNA (Tanna. T, Sachan. V, 2014).

In the past it was thought that the relative spatial selectivity of neurodegeneration in HD is why early studies into using fetal striatal cells were effective in rodent and primate models with HD. Some proposed treatments for HD are specific to human CNS/ tissue due most animal models being vastly different in terms of neural complexity which is hard to research. For obvious reasons access to HD human brain tissue is limited to post mortem samples, however HD specific hPSCs neural derivatives could be an ideal candidate to overcome this problem though developing HD affected cerebroids. Some research has used HD-PSCs for researching HD due to their 3 main advantages:

1. HD-hPSCs derivatives carry exact genomic content for HTT.

2. They provide unlimited access to phenotypically relevant cell including post mitotic neurons.

3. They feature mutation induced functional impairments, correction of which using gene therapies allow for testing of their actual therapeutic quality before clinical trials.

One weakness at this time is a lack of real clinical results in human testing (Perrier. A, Peschanski. M, 2012).

Treating Parkinson’s disease

Parkinson’s disease (PD) deals with the loss of dopaminergic neurons within the substantia nigra and is currently the most prevalent neurodegenerative disease. MSCs can be differentiated into dopaminergic neuron cells using various strategies such as gene transfer of notch intracellular domain and the treated with glial cell line derived neurotrophic factors. Ince transplanted studies have shown to cause significant improvement in rotational behaviour in rat models. Another study showed human UC-MSCs get converted into dopaminergic neurons via transfer of Lmx1a and neurturin genes in vitro which showed positive results when transplanted into a rhesus monkey model. One problem with MSC transplantation is contamination with fibroblasts have been shown to accelerate neurodegeneration in mouse PD models. Another problem is host to graft disease propagation due to the tendency of MSCs to be highly interactive with their host microenvironment (Tanna. T, Sachan. V, 2014, Dantuma. E, et al, 2010).

Another study proposed using ESC for cell replacement therapy, it showed highly enriched population of midbrain NSCs can be derived from mouse ESCs. Dopamine neurons generated by these stem cells show electrophysiological and behavioural properties expected from neurons in the midbrain. It has also been proposed that the use of IPSCs derived from mouse fibroblasts to produce multipotent neuronal progenitor cells for injection into PD models. Injected IPSCs were shown to migrate to different areas of the brain, were they differentiate into glia and neurons once integrated into the host brain (Dantuma. E, et al, 2010).

Lou Gehrig’s disease

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that mostly effect motor neurons in the spinal cord, brain stem, and motor cortex. This leads to progressive paralysis in patients. Out of the five motor neurone diseases it is the most common and leads to death up to 5 years after onset. HMSCs have been used as delivery vectors for glial cell line derives neurotrophic factor (VEGF) into muscle tissue of rats with ALS which then show improvement in motor functions. Lumbar injections of HMSCs have been shown to reduce motor neurone loss, inflammation, and functional impairment in mouse models. Also, intraspinal injections of autologous MSCs have been shown to be safe and hold Therapeutic potential in clinical trials. ad MScs after transplantation have shown characteristics of delaying motor deterioration and ameliorating clinical and pathological features due to their immunomodulative and neuroprotective characteristics. IPSCs derived from patients have been shown to differentiate into motor neurons, giving use to potential autologous transplantation (Tanna. T, Sachan. V, 2014).

A study into treating Lou Gehrig’s disease by transplanting NSCs which were positive for both Lewis x and chemokine receptors into a spinal cord. Disease progression was shown to be delayed and survival time in transplanted mice was shown to increase due to presence of integrated cells in their spinal cord. Though some disputes arise from the idea of replacing degenerating motor neurons due some lack of knowledge on whether patients will produce healthy neurons from these transplanted cells. Though a study in 2008 showed stem cells were safe in a clinical setting for ALS patients however this study was limited by its small sample size (Dantuma. E, et al, 2010).

Treating multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterised by the by demyelination, inflammation and formation of plaques in the CNS along with axonal loss leading to severe disability. As such this condition is classified as both an autoimmune disease and a neurodegenerative disease. Stem cells have shown great promise for MS therapies particularly hematopoietic stem cells (HSCs) which have been tested in both animal models and clinical trials. MSC transplantation has been the focus of numerous studies showing the potential to ameliorate inflammation due to MSC’s immunomodulatory effects. This can foster tissue repair and regeneration through neuroprotective and neurodegenerative qualities (Tanna. T, Sachan. V, 2014). Some studies looked into transplanting myelin forming cells into sites of damage to existing myelin sheaths. One limitation of this however is that in the past there was a problem with limited supply of lineage specific myelin forming cells. Therefore, IPSCs may be the best way to slow degradation (Dantuma. E, et al, 2010).

Using stem cell derived exosomes in place of stem cells

Due to the drawback of MSCs that being instant blood mediated inflammatory responses which are an innate immune reaction to cell graft upon blood contact. This leads to coagulant activation and effector cell engagement to sequester and destroy administered MSCs due to potential incompatibility with host blood. Cell free therapies utilise MSC secreted exosomes which are sphere shaped vesicles that contain combinations of cell specific biomolecules. These basically inherit the therapeutic qualities properties of their parent cells, this exosome therapy which involve exosomes taken from stem cells is considered preferable due to advantages over stem cells:

• Non toxicity

• Non immunogenicity

• Lack of tumour genic qualities

• Less effort to preserve

Their main therapeutic benefits include their ability to secrete immune and trophic factors to stimulate endogenous repair mechanisms at target sites. This includes exosomes that contain mRNA and regulatory miRNA, TRNA signalling lipids, growth factors, cytokines and mitochondrial DNA. To facilitate post-transplant detection of MSCs they are labelled with nano particles such as iron oxide. The presence of iron oxide nano particles in exosomes has two benefits, firstly they act as a magnet to guide navigation of exosomes to target cells. Secondary the iron oxide will ionise to iron ions alongside the activation of C- JUN and JNK signalling pathways to allow the exosomes to carry a large number of therapeutic factors. These exosomes have been seen to help neurodegenerative conditions such as spinal injury, ischemic strokes and can help prevent tumour angiogenesis in mouse models (Mehta. K. J, 2025).

Conclusions

Looking at the different conditions it can be inferred that stem cell treatments can help repair damage caused to the CNS to all of them. MSCs seem to be the most promising type of stem cell for treating these conditions due to their ease of acquisition and their innate ability to migrate to areas of cellular damage. Using MSCs or NSCs seemed to have the best overall results in animal models though more research needs to be done in clinical settings due to unique elements of the human CNS. One problem is the various ethical and logistical problems with live human testing especially acquiring volunteers who are suffering with conditions which can affect their decision making such as Alzheimer’s disease. A way around this could be to utilise human derived neural organoids as a research model though this technology is still in its relative infancy so will also require further development. Two major drawbacks that need to be addressed are potential host rejection and tumour genesis. Host rejection could be solved by generating stem cells from host tissue to make them more compatible with the patient’s unique physiology. The development of tumours is the most concerning side effect though exosomes however may already be a way to circumvent this as an alternative to using whole stem cells. Exosome development may present an exiting new area of medical research in the coming years and may open new avenues of treatment that even stem cells where able to.

Glossary

Astrocytes: a type of star shaped glial cell that support nerve cells.

Fibroblast: a type of cell that helps with formation of connective tissue to aid structural framework of tissues.

Glasgow coma scale: a tool used to asses a patient’s level of cognitive function using a 1-15 scale, it takes a variety of factors into account such as eye movement, verbal and motor responses.

Glial cells: a group of cell types responsible for holding neural cells in place to aid in their proper function.

Neurogenesis: the process where new neurons are created in the brain and the CNS.

Teratoma: a form of tumour composed of cell types not normally found at the site of formation.

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