Introduction
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms (tremor, rigidity, bradykinesia) and non-motor or premotor symptoms (NMS) such as depression, anxiety, sleep disturbances, and cognitive decline. These non-motor manifestations often appear years before classical motor signs, indicating a prolonged prodromal phase of neurodegeneration.
Recent advances in regenerative medicine highlight Mesenchymal Stem Cell (MSC) therapy as a potential biotherapeutic approach for both motor and non-motor phases of PD. This literature review examines how MSC Stem Cell contribute to neuroprotection, immune regulation, and neurovascular repairม especially targeting early or premotor stages where conventional drugs have limited efficacy.
Pathophysiology of Parkinson’s Disease and Premotor Symptoms
The hallmark pathology of PD is the degeneration of dopaminergic neurons in the substantia nigra and accumulation of α-synuclein aggregates (Lewy bodies). However, mounting evidence shows that non-motor symptoms—such as anxiety, fatigue, and depression—precede motor dysfunction by several years.
These symptoms correlate with neuroinflammation, mitochondrial dysfunction, and synaptic disconnection rather than dopamine depletion alone. Activation of microglia and astrocytes, release of pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ), and damage to the blood–brain barrier create a toxic cycle that accelerates neuronal loss.
This inflammatory state is also linked to gut–brain axis dysfunction and altered microbiota, which can exacerbate anxiety, constipation, and sleep problems long before PD motor symptoms emerge.
Current Treatment Limitations
Conventional PD management relies on levodopa therapy, dopamine agonists, and deep brain stimulation (DBS)—interventions that improve motor symptoms but often worsen or neglect non-motor issues.
Antidepressants (SSRIs, SNRIs, TCAs) provide limited benefit and may aggravate tremor or induce metabolic side effects. Similarly, medications for sleep, urinary, or cognitive symptoms often yield inconsistent results.
This unmet therapeutic gap has led to increasing interest in biotherapy, specifically MSC Stem Cell transplantation, for holistic symptom control and neural protection in early PD.
Mechanisms of Mesenchymal Stem Cell Action
MSC Stem Cell, derived from bone marrow, adipose tissue, or umbilical cord (UC-MSC Stem Cell), exhibit potent paracrine, anti-inflammatory, and regenerative properties.
Their therapeutic mechanisms include:
- Neuroprotection and Dopamine Restoration – MSC Stem Cell secrete neurotrophic factors such as BDNF, GDNF, and VEGF that protect dopaminergic neurons and promote new axonal connections.
- Immunomodulation – MSC Stem Cell suppress overactive immune cells (microglia and T cells), lower pro-inflammatory cytokine levels, and shift the immune balance toward anti-inflammatory states.
- Angiogenesis and Neurovascular Repair – Growth factors secreted by MSC Stem Cell enhance local blood flow, promote endothelial cell survival, and strengthen the neurovascular unit, vital for neuron maintenance.
- Mitochondrial Support – MSC Stem Cell transfer healthy mitochondria to stressed neurons, improving energy metabolism and reducing oxidative stress.
- Synaptic Plasticity and Regeneration – Through exosome and microvesicle release, MSC Stem Cell deliver miRNAs and proteins that stimulate synaptogenesis and neuronal differentiation.
These multifaceted effects make MSC Stem Cell particularly promising for premotor symptoms such as depression, anxiety, fatigue, and cognitive impairment.
Evidence from Preclinical and Clinical Studies
Animal Studies
In PD models induced by neurotoxins (e.g., 6-OHDA, MPTP), intravenous (IV), intranasal, and intrathecal MSC transplantation improved motor function and reduced neuroinflammatory markers.
Rats receiving UC-MSC injections exhibited increased tyrosine hydroxylase (TH) expression in the striatum—indicating dopamine restoration—along with better locomotion and reduced anxiety-like behavior.
Other studies showed that MSC-derived exosomes promoted dopaminergic neuron survival and decreased α-synuclein aggregation.
Clinical Trials
Several human studies have validated the safety and feasibility of MSC Stem Cell therapy:
- Intravenous MSC infusions in PD patients improved UPDRS (Unified Parkinson’s Disease Rating Scale) motor scores and cognitive function without major adverse effects.
- Subarachnoid and carotid artery infusions demonstrated up to 80% improvement in motor performance within 1–3 months, with sustained benefits for up to 36 months in some cohorts.
- A growing number of Phase I/II clinical trials (e.g., NCT04146519, NCT04995081) are now assessing MSC Stem Cell for both motor and non-motor PD symptoms, especially depression and sleep disorders.
MSC Biotherapy for Depression and Premotor Symptoms
Depression is one of the most disabling premotor symptoms of PD, often linked to hippocampal atrophy and neurogenesis impairment. Traditional antidepressants show limited success in this population.
MSC Stem Cell offer an innovative biological alternative by stimulating hippocampal neurogenesis, enhancing brain-derived neurotrophic factor (BDNF) production, and reducing neuroinflammatory cytokines such as IL-6 and TNF-α.
Experimental evidence in chronic stress models indicates that MSC Stem Cell transplantation into the hippocampus or via nasal administration can reverse depressive-like behaviors, improve learning and memory, and normalize hypothalamic–pituitary–adrenal (HPA) axis function.
This nasal-brain delivery route bypasses the blood–brain barrier, enabling noninvasive and repeated stem cell administration—a potential breakthrough for PD-related depression and anxiety management.
Innovations and Gene-Modified MSC Strategies
Recent studies combine MSC Stem Cell therapy with genetic or pharmacologic preconditioning to enhance therapeutic outcomes. For example:
- MSC Stem Cell genetically modified to express Nurr1 or tyrosine hydroxylase show superior dopaminergic neuron regeneration and dopamine release.
- Pre-treatment with pleiotrophin or hypoxic conditioning improves MSC survival, adaptation, and trophic factor secretion post-transplant.
- MSC-exosome therapy offers a cell-free approach, delivering active regenerative molecules without the risks associated with whole-cell transplantation.
Such enhancements could significantly improve clinical efficacy in PD premotor and motor phases alike.
Challenges and Future Directions
Despite encouraging progress, several challenges remain before MSC biotherapy becomes mainstream for PD:
- Standardization – Differences in cell sources, culture protocols, and delivery methods make it difficult to compare results across studies.
- Long-Term Efficacy – The survival rate of transplanted cells rarely exceeds 5% without supportive scaffolds or gene modifications.
- Dose Optimization – The ideal dosage and timing for repeated administration remain undefined.
- Regulatory and Ethical Oversight – As PD therapies evolve toward early intervention, rigorous safety monitoring and transparent communication with patients are essential.
Future research is focusing on MSC-exosome products, combination therapies with probiotics or neurorehabilitation, and personalized protocols integrating biological markers for disease stage and symptom type.
Conclusion
Mesenchymal stem cell therapy represents a transformative avenue for addressing both motor and non-motor dimensions of Parkinson’s Disease.
By restoring neurovascular balance, reducing neuroinflammation, and promoting neuronal survival, MSC-based biotherapy holds the potential not only to slow disease progression but also to improve quality of life in the premotor stage, when early intervention can make the greatest impact.
In particular, umbilical cord–derived MSC Stem Cell (UC-MSC Stem Cell) combine safety, scalability, and immunomodulatory strength, positioning them as ideal candidates for future clinical applications in Parkinson’s disease management—especially within global centers of regenerative medicine such as Thailand, where GMP-certified laboratories and advanced biotherapy programs are rapidly expanding.