Parkinson’s disease (PD) is one of the most common neurodegenerative conditions, second only to Alzheimer’s. It primarily affects the basal nuclei of the brain, leading to the gradual loss of dopamine-producing neurons and the buildup of abnormal protein clusters called Lewy bodies. Together, these changes cause the classic motor and cognitive symptoms of the disease. PD affects about 1% of people over age 50 and nearly 2.5% of those over age 70. Men face a slightly higher lifetime risk than women. While some cases of PD are linked to inherited genetic mutations, most are considered “sporadic,” arising from a mix of genetic and environmental factors.
Researchers have identified several genes that can contribute to PD, including those related to alpha-synuclein (aSyn), PINK1, Parkin, LRRK2, and others. These discoveries, along with the study of biomarkers, have created opportunities for earlier detection. At the same time, scientists have uncovered lifestyle factors that influence risk. For example, smoking and caffeine consumption are linked to a lower likelihood of developing PD, while oxidative stress, free radical damage, and environmental pollutants can increase risk.
The hallmark motor symptoms of PD include slowness of movement (bradykinesia), muscle rigidity, resting tremor, and impaired balance. Non-motor symptoms such as sleep disturbances, loss of smell, constipation, depression, and cognitive changes often appear years before movement-related issues and can worsen over time. Although medications such as levodopa and dopamine agonists are effective at easing symptoms, they cannot halt or reverse the underlying degeneration. This is why there is a strong need for new therapies aimed at protecting or replacing dopamine-producing neurons.
Here, Unnisa et al. review the MSC-based treatment in Parkinson’s disease and the various mechanisms it repairs in parkinsonian patients.
Why Stem Cell Therapy is Being Explored
Neurodegenerative diseases like PD involve the progressive death of nerve cells. Importantly, research shows that neurons begin to lose their function well before they die. This insight has shifted the focus away from simply preventing cell death to finding ways to repair and restore neurons. Stem cell therapy is one of the most promising strategies.
The concept is not new. In the late 1970s, researchers transplanted dopamine-producing neurons from prenatal rats into rat models of Parkinson’s, which successfully improved motor impairments. This early work laid the foundation for today’s efforts, which now center on the use of mesenchymal stem cells (MSCs).
MSCs are attractive because they are abundant in the body, can self-renew, and have the ability to transform into different types of cells, including neurons. They also release a variety of molecules that promote healing, reduce inflammation, and support tissue repair.
The Potential Role of MSCs in Parkinson’s
MSCs have been used in studies to treat conditions ranging from spinal cord injuries and heart attacks to autoimmune diseases and chronic wounds. In PD research, MSCs are being explored for their ability to restore lost dopamine neurons and improve function.
Once mobilized to a site of injury, MSCs activate multiple repair mechanisms. They release protective neurotrophic and growth factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), and others. These molecules can protect neurons from further damage, promote survival, and encourage regeneration. MSCs also secrete anti-inflammatory cytokines, reducing harmful immune activity, while suppressing pro-inflammatory molecules that are elevated in PD.
Beyond their chemical signaling, MSCs demonstrate remarkable flexibility. They can differentiate into dopamine-producing neuron precursors, supply damaged cells with healthy mitochondria, and even enhance processes like autophagy—the natural cellular “clean-up” system that helps prevent toxic protein accumulation. Animal studies show that MSCs transplanted into models of PD can migrate to damaged areas, reduce inflammation, improve motor function, and increase dopamine levels without forming tumors.
From Induction to Transplantation
MSCs can be derived from several tissues, including bone marrow and adipose tissue. In the laboratory, they can be guided through a process called induction to become dopamine-producing neurons. This often involves exposure to specific growth factors and signaling molecules that encourage the cells to take on neuronal properties.
Once prepared, the induced cells can be transplanted into affected brain regions such as the striatum. In animal models, transplanted MSCs not only survive but also integrate into the host brain, enhance neurogenesis, reduce damaging immune responses, and boost dopamine production. Studies have found no evidence of tumor formation in these experiments, supporting the safety of this approach.
How MSCs May Repair Neurons
The benefits of MSC therapy appear to arise from several overlapping mechanisms. The authors describe two main effects: the secretion of trophic and protective factors, and the direct differentiation of MSCs into replacement cells. The cells influence their environment in multiple ways, often through paracrine signaling—sending out chemical messengers that alter the behavior of nearby cells.
MSCs may differentiate into neuron-like cells, particularly when exposed to supportive conditions such as co-culture with glial cells or stimulation with neurotrophic factors. They can also fuse with host cells to enhance their survival. Meanwhile, the wide range of growth factors and cytokines secreted by MSCs helps protect dopamine neurons, support new blood vessel growth, and activate the brain’s own neural stem cells.
Another key role is immunomodulation. PD involves an inflammatory component, with elevated cytokines and immune activity in the brain. MSCs help by suppressing overactive immune cells, releasing anti-inflammatory mediators, and reducing oxidative stress. They can even interact directly with antigen-presenting cells, shifting the immune response in a way that protects neurons.
Finally, MSCs demonstrate a homing ability—they can migrate through the bloodstream and cross into tissues where they are most needed. This process is influenced by factors such as donor age, culture conditions, and the method of delivery.
Challenges and Limitations
While MSC therapy for PD is highly promising, there are still limitations. The beneficial effects observed in many studies are often temporary, as MSCs do not always survive long-term or integrate fully into the brain.
Another challenge is the variability of MSC populations. These cells are typically identified by their ability to stick to culture surfaces, but they are not a single uniform type. This lack of a definitive molecular marker makes it difficult to predict or control how they will behave. Additionally, while MSCs can be coaxed to differentiate into dopamine-producing neurons, the efficiency of this process is relatively low. Identifying the specific subgroups of MSCs most capable of neuronal differentiation could improve outcomes.
Despite these limitations, MSCs remain a realistic therapeutic option. They are relatively easy to obtain from patients or donors, carry fewer ethical concerns compared to embryonic stem cells, and have already been used safely in other clinical settings such as heart disease and osteoarthritis. Their versatility, safety profile, and broad mechanisms of action make them strong candidates for further development.
Looking Ahead
Parkinson’s disease remains a devastating, progressive disorder without a cure. Current treatments manage symptoms but cannot stop or reverse the loss of dopamine neurons. Mesenchymal stem cells offer a new approach, with the potential to protect, repair, and even replace damaged neurons through multiple pathways.
While research is still in early stages, findings so far are encouraging. MSCs can reduce inflammation, protect dopamine neurons from death, restore mitochondrial health, and promote the growth of new neural connections. Importantly, they have demonstrated safety in clinical and preclinical studies. However, long-term monitoring and larger clinical trials are needed to determine the best methods for preparing, delivering, and sustaining these cells.
Future work will likely focus on refining induction techniques, identifying the most effective MSC subtypes, and combining cell therapy with other approaches such as gene therapy or neuroprotective drugs. With continued progress, Unnisa et al. conclude that MSC-based treatments may one day shift the outlook for people living with Parkinson’s, offering not just symptom relief but a real chance at slowing or even reversing the disease.
Source: Unnisa A, Dua K, Kamal MA. Mechanism of Mesenchymal Stem Cells as a Multitarget Disease- Modifying Therapy for Parkinson’s Disease. Curr Neuropharmacol. 2023;21(4):988-1000. doi: 10.2174/1570159X20666220327212414. PMID: 35339180; PMCID: PMC10227913.
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