Regenerative Medicine for Parkinson's Disease

Mesenchymal stem cell-derived exosomes (MSC-Exos) are nano-sized extracellular vesicles with low immunogenicity. They have the ability to transfer active molecular substances formed by our stem cells. Experimental studies have demonstrated MSC-Exos have effects on many diseases. 

As the second most prevalent neurodegenerative disease worldwide, Parkinson’s disease (PD) is characterized by severe progressive motor dysfunction caused by loss of dopaminergic neurons (DAn) and dopamine depletion. MSC-Exos serve as a promoter of neuroprotection and neural differentiation. They are promising therapeutic agents in the setting of PD. 

Parkinson's disease (PD) is a neurodegenerative disorder first described by James Parkinson in 1817. As the global population ages, neurodegenerative diseases are becoming a significant cause of mortality, with PD being a prominent example. It affects around 1-2% of the elderly population, impacting over 10 million individuals worldwide. PD has various clinical symptoms, including motor issues like rigidity, resting tremors, bradykinesia, akinesia, postural instability, and gait problems. Non-motor symptoms such as sleep disturbances, depression, dementia, and peripheral injuries are common.

The pathological hallmark of PD is the progressive degeneration of dopaminergic neurons (DAn) in a brain region called the substantia nigra (SN). This degeneration is associated with the accumulation of protein aggregates known as Lewy bodies (LB), abnormal accumulations containing α-synuclein, along with a reduction in dopamine production in the brain. 

While some diagnostic tests and imaging techniques like Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) aid in diagnosing PD, clinical judgment remains pivotal in its identification and treatment. 

Therapies primarily targeting dopamine levels, such as deep brain stimulation (DBS) and pharmacological treatments using dopamine substitutes like Levodopa preparations, dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors, are available  These treatments offer only symptomatic relief in the early stages and do not address the progressive degenerative nature of PD, leading to limited disease modification and potential adverse effects on the patient's quality of life.

Among various stem cell-based therapies, the use of mesenchymal stem cells (MSCs) shows great promise in combating PD. MSCs can be easily obtained from several sources in the body, including bone marrow, adipose tissue, umbilical cord-derived Wharton's jelly, peripheral blood, brain, and dental pulp. MSCs possess low immunogenicity and potent regenerative abilities, capable of differentiating into various cell types. MSCs have significantly affected PD progression in animal models and some clinical trials involving mild to moderate PD patients. These effects are attributed, in part, to the secretion of various factors such as neurotrophins, growth factors, and regulatory micro-RNA molecules.

Recent research has unveiled that the therapeutic benefits of MSCs are mediated by the release of extracellular vesicles (EVs), particularly exosomes. Exosomes are the smallest subgroup of EVs and have been identified in various body fluids and tissues. They play a crucial role in cell-to-cell communication, influencing physiological processes. Studies have shown that exosomes derived from MSCs exert notable effects on neurological disorders, particularly neurodegenerative diseases such as PD. In this review, we will explore the potential of exosomes from MSCs as a therapeutic approach for PD, examining the underlying mechanisms that make them promising candidates for treating this complex disease.

Exosomes:

Exosomes were first discovered in 1983 during studies on maturing sheep cells. Later, scientists found that all cells in the body, like tumor cells, immune cells, neurons, and others, can release these tiny particles. They can be found in various body fluids like blood, urine, and cerebrospinal fluid.

Exosomes are a type of small extracellular vesicle (EV), the smallest EVs ranging from 30 to 150 nanometers. Depending on the cells they come from, they carry different molecules like proteins, RNA, and genetic material.

Structurally, exosomes have a membrane made of lipids, which keeps them stable. They contain proteins, nucleic acids, and some proteins and lipids on the membrane. These proteins help with cell communication and other functions.

Treatment of PD With MSCs:

Studies have shown that mesenchymal stem cells (MSCs) can be helpful in treating PD. MSCs taken from bone marrow, adipose tissue, or umbilical cord and directly given to the brain in animal studies improved motor function and brain cell survival.

In human PD patients, infusions of MSCs have also shown improvements in motor and nonmotor symptoms. However, there are still challenges with the best cell sources, doses, and administration methods.

The potential of MSC-derived exosomes in PD:

Scientists are exploring using substances released by MSCs, especially exosomes, as a treatment for PD without using actual cells. These exosomes have shown protective effects in animal models of PD.

Exosomes from different sources have also been found to protect brain cells and improve symptoms in PD models. They contain various neuroregulatory products that may be helpful. 

Using exosomes separated from MSCs as a cell-free treatment for PD is currently being advanced as a safer means of achieving similar outcomes to those of MSCs. These tiny particles show promise in treating various diseases, including PD.

In conclusion, MSCs' exosomes have great potential for treating Parkinson's disease. Further research is needed to understand their exact mechanisms and to optimize their use as a therapy for PD patients.

In a study of the neuroprotective effects comparison between human bone marrow-derived MSC (hBM-MSCs) and the secretome derived from them, the secretome(exosomes and microvesicles) has better effects on protecting dopaminergic neurons, neuronal differentiation and survival than hBM-MSCs. 

Mechanism of MSC-derived Exosomes in Treating Parkinson's Disease (PD):

Advantages of using MSC-exos: 

They cross the blood-brain barrier (BBB): The BBB is a protective barrier in the brain that prevents large molecules from entering, making it challenging to deliver therapeutic drugs for neurological diseases.

Exosomes interact with cells in various ways: 

Adhere to the cell surface and fuse with it, releasing its contents and triggering biological processes. 

Associate with specific cell surface proteins and initiate signal cascade reactions. Additionally, they can cross the BBB through different processes.  Surface markers on exosomes play a key role in interacting with target cells. Once they cross the BBB, exosomes may release their contents into the receiving cell's cytoplasm, initiating signal transduction. They can also reach the cell membrane, where they form new exosomes to interact with adjacent cells, or lysosomes can break them down.

Another important mechanism of exosome signaling involves a class of molecules called miRNAs. These are noncoding RNAs that regulate the expression of target genes. In PD, there are dysregulations in the expression of specific miRNAs linked to the disease's progression. These miRNAs can affect the levels of crucial proteins in PD, such as a-synuclein, LRRK2, PRKN, and PARK7, which play key roles in the disease's pathogenesis.

Exosomes derived from MSCs can serve therapeutically as novel carriers for protective/repairing miRNAs, delivering them to target cells in the brain by crossing the BBB. Some miRNAs, like miR-133, are important for developing dopamine-producing neurons and can promote neurite outgrowth. Other miRNAs, such as miR-143, miR-21, miR-17, miR-18a, miR-19a/b, miR-20a, and miR-90a, can modulate immune response, neurogenesis, axonal growth, and neuronal death.

Studies have shown that MSC-exos positively impact PD models and specific miRNAs like miR-7 and miR-124 have been found to have beneficial effects.  More research is needed to fully understand how these miRNAs function and interact with target cells in PD. Despite these challenges, MSC-exos hold great promise as a potential clinical therapy for PD and other central nervous system diseases.

The mechanism of MSC-derived exosomes in treating PD lies in their ability to cross the BBB and deliver therapeutic miRNAs to affected brain areas. These exosomes can alleviate neuroinflammation, reduce cell death, and regulate cellular processes like autophagy. With more research, exosomes could become a valuable treatment option for PD and other degenerative neurological conditions.

At Infinite Health Integrative Medicine Center, we see transformational results in our patients receiving MSC-exo for Parkinson's disease treatment. If you would like more information and/or to find out if you or your loved one qualifies, visit www.YourInfiniteHealth.com or call 504-323-0025 to speak to one of our wellness coordinators.