Mesenchymal stem cell-derived exosomes as a promising therapy for Parkinson’s and Alzheimer’s Disease.
Recently, investigators suggested using Mesenchymal stem cells (MSCs)–derived exosomes as a therapy for different conditions, including Parkinson’s Disease (PD). [1,2,5] MSCs can be found in various body parts and specialize in different cell types depending on the body’s needs. [1] These cells produce extracellular vesicles called exosomes that have been studied as an alternative medicinal agent because of their stability and biological prospect in terms of the substances they carry, like signaling molecules, cytokines, enzymes, and micro-RNA (miRNA). [1,2,4] All these components are essential in maintaining cellular homeostasis, while the miRNA is more involved in regulating gene expression. [1,2,4] Many studies with MSCs have demonstrated several benefits in other neuropathological conditions. [1] One of the insights is that the MSCs have been pointed to activate different neuro-regeneration processes, opening a door for many possible ways to serve as promising therapies for future clinical trials. [1,3] Two targets for developing new treatments using MSCs are PD and Alzheimer’s disease (AD). [2,3,4,7] PD is characterized by the deterioration of dopaminergic neurons and the insufficiency of dopamine production. [3,6,9] Generally, the decrease of dopaminergic neurons is related to the accumulation of Lewy bodies (protein aggregates of α-synuclein) inside the neurons, which affects the normal functioning of those cells. [9] Interestingly, MSCs-derived exosome seems to be able to decrease one of the leading causes of PD, neuroinflammation. [2,5,10] On the other hand, AD is described as a brain illness that presents as neurological hallmarks the formation of amyloid plaques (Aβ) and neurofibrillary tangles causing synaptic loss. [4,7,12]
One principal characteristic that makes MSCs so promising is their availability in the human body (brain, adipose tissue, dental pulp, bone marrow, placenta, and the umbilical cord). [1] However, it is vital to address that although all these cell populations are defined as MSCs, they present differences, especially in their antigen markers composition. [1] For this reason, several studies show differences in each MSCs isolation, cell culture, and expansion protocols. [1] MSCs release a product called secretomes into the extracellular space, composed of chemokines, growth factors, cytokines, extracellular vesicles, and proteins that promote neuroprotection, neural differentiation, and the decrease of neuroinflammation. [1,2,8] This characteristic makes the MSC-secretome a promising therapeutic option for treating neurodegenerative disorders. [1] Several investigations have demonstrated remarkable MSCs’ capacity to cross the blood-brain barrier (BBB), long half-life, and low immunogenicity. [1,7,8] Also, some research shows an inflammation reduction after MSCs-derived exosome administration in a traumatic brain injury model. [2,5] In addition, the MSCs-derived exosome injection promotes neuro-regeneration and reduces inflammation in rat models after injury. [1,2,5] Also, MSCs promote neuroprotection, neural differentiation, and immunomodulation after intracranial transplantation. [1,2,5] Even though the MSCs-derived exosomes have many benefits, the most relevant insight demonstrated by several studies is their high levels of an amyloid β-degrading enzyme (neprilysin), which decrease Aβ levels, thus having an incredible impact on slowing the Alzheimer’sAlzheimer’s disease progression. [4,7,8,12] Also, evidence suggests an essential role of autophagy in AD, where dysfunction in this system can lead to Aβ accumulation. [8,13,14] MSCs have been tested in vivo and in vitro AD models where the administration of MSCs has increased autophagy meaningfully, thus reducing the Aβ levels and increasing neuron survival. [13] MSCs demonstrate to improve neurogenesis and enhance memory deficits in both animal and cellular models of AD. [8,13]
On the other hand, MSC can communicate and diffuse MSC-secretome with nearby cells like neurons. [1,4] This is important since it raises the chances of a noninvasive treatment administration and the delivery of molecules of interest using an easy and more direct route. [1,15] The differentiation ability into various neurons shows that MSC can replace dead cells, especially in affected regions (see Figure1). [15] Other MSCs-derived exosome components described in many articles, like miR-143 and miR-21, have a crucial role in immune response modulation and neuronal death related to chronic inflammation (see Figure1). [15] Also, MSCs-derived exosomes help modulate neurogenesis, axonal growth, and CNS recuperation. [15] In PD mice models, MSCs-derived exosomes cause behavioral improvements and suppress some of the α-synuclein components in its pathway, decreasing α-synuclein production. [15] There are different routes for MSC administration in PD treatment. [15] The first one is the direct transplantation of these cells into the affected location. [8,15] This technique has shown advantageous outcomes, especially in the subthalamic nucleus, substantia nigra, and striatum. [8,15] Recent studies discover the MSC’s capacity to migrate to injury locations, promoting repair. [8,12,15] This finding expands the MSC administration, and new noninvasive methods like intranasal administration are also available, showing promising results. [1,15] Preclinical PD models using intranasal administration demonstrated the effective delivery of MSCs to brain areas like the olfactory bulb, hippocampus, striatum, cerebellum, brain stem, amygdala, and spinal cord even four months after the injection (see Table 1 & 2). [3,5] Even though there is a lot of good data from in vitro and in vivo models, only a few clinical studies for AD are currently listed in the National Institutes of Health clinical trials database (see Table 3). [4] Only one clinical trial was approved to analyze the safety and effectiveness of MSC-derived in humans with mild to moderate dementia (NCT04388982). [4]
Appendix
Table 1. Clinical Trials Using Mesenchymal Stem Cells for Treatment of Parkinson Disease (Clinicaltrials.gov)
Figure 1. Schematic representation of the active role of exosomes on PD
Table 2. Clinical trials undertaken with MSCs in neural repair (www://ClinicalTrials.org)
Table 3. Summary of preclinical studies of MSC-derived EVs-based therapy both in vitro and in vivo models of AD
