Therapeutic Potential of MSC-EVs in Neurodegenerative Disorders: History
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Contributor:
Ermanna Turano
,
Ilaria Scambi
,
Federica Virla
,
Bruno Bonetti
,
Raffaella Mariotti

The application of mesenchymal stem cells (MSCs) represents a new promising approach for treating neurodegenerative diseases. Growing evidence suggests that the therapeutic effects of MSCs are due to the secretion of neurotrophic molecules through extracellular vesicles. The extracellular vesicles produced by MSCs (MSC-EVs) have valuable innate properties deriving from parental cells and could be exploited as cell-free treatments for many neurological diseases.

  • mesenchymal stem cells
  • extracellular vesicles
  • exosomes
  • neurodegenerative disease

1. Introduction

The treatment of most neurological disorders currently represents a therapeutic challenge for the researchers committed to improving and/or extending the quality and lifespan of affected people.
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by the accumulation of specific proteins within the nervous system accompanied by a progressive loss of neurons in the affected regions [1][2]. The pathogenic mechanisms are still unclear and the failure to identify the precise causes of neuronal degeneration leads to the absence of treatments [3].
The use of stem cells was considered a potentially suitable strategy for the treatment of neurodegenerative disorders. Stem cells are undifferentiated totipotent or multipotent cells that can be obtained from a variety of adult tissues such as bone marrow, brain, liver, skin, skeletal muscle, gastrointestinal tract, pancreas, eye, blood, fat, and dental pulp [4]. The mesenchymal stem cells (MSCs) can differentiate to osteoblasts, adipocytes, and chondrocytes in vitro [5]. Due to their capacity to transdifferentiate in vitro into epithelial cells and lineages derived from the neuroectoderm, MSCs have been considered to be able to repair injured, damaged, or diseased tissues [6]. Moreover, MSCs possess the important ability to modulate the immune response of a broad range of immune cells, both in vitro and in vivo [7][8][9][10]. The use of MSCs for tissue repair requires such cells to be able to easily access the target organ. Several works have demonstrated their ability to home into the damaged brain, migrating from the blood toward inflamed tissues where they exert a neuroprotective effect [11][12][13].
The efficacy of MSCs in neurological diseases was demonstrated in several preclinical studies [14][15]. However, despite their therapeutic action, the engraftment of MSCs in central nervous system (CNS) tissues, after their transplantation, results in a small percentage of differentiated, detectable MSCs [16][17]. These considerations suggest that the ability of MSCs to modify the tissue microenvironment via secretion of soluble factors may contribute more significantly to tissue repair than their capacity of transdifferentiation [18][19][20][21].
Such action is achieved through a paracrine mechanism, the release of extracellular vesicles (EVs), which is, indeed, common to almost all cells. EVs are membranous structures derived from the endosomal system or shedding from the plasma membrane [22][23][24][25] whose release and uptake provide a novel mechanism of transcellular communication [26][27]. MSCs are also able to release a large number of EVs with high therapeutic power which constitute an effective alternative to cell-therapy in neurodegenerative diseases, due to their content which can reproduce the effect of their parental cells [28][29][30] (Figure 1). Indeed, MSC-EVs contain many neurotrophic factors (NTFs), immunomodulatory and anti-inflammatory molecules including transforming growth factor-β (TGF-β), and interleukin-10 (IL-10), which are involved in favoring the processes of neurogenesis and neuroprotection and promote functional recovery [31][32][33]. Interestingly, proteins involved in neural development and synaptogenesis, such as nestin, growth-associated protein 43 (GAP-43), and synaptophysin are incorporated in MSC-EVs [34]. Moreover, in terms of miRNA content, a specific signature of miRNAs was reported, which was implicated in promoting CNS recovery by modulating neurogenesis and stimulating axonal growth [35].
Figure 1. Extracellular vesicles from mesenchymal stem cells as an innovative therapy for neurodegenerative disease. MSC-EVs derived from different cellular sources, due to their small size, cross the blood–brain barrier and reach the affected cells of the diseased brain. Here, EVs release neurotrophic factors (NTFs), miRNA, and anti-inflammatory molecules that mediate neuroprotection, neurogenesis, synaptogenesis, and decrease the neuroinflammation. EVs with their cargo contribute to a functional recovery and neurodegeneration reduction. BBB = blood–brain barrier; NTFs = neurotrophic factors; TGF-β = transforming growth factor-β; IL-10 = interleukin-10; GAP-43 = growth-associated protein-43; SYP = synaptophysin; ROS = reactive oxygen species; iNOS = inducible nitric oxide synthase; M1 = pro-inflammatory M1-polarized microglia; M2 = anti-inflammatory M2-polarized microglia.
In 2018, the International Society for Extracellular vesicles (ISEV) updated the guidelines for the study of EVs. They are a heterogeneous population whose size may vary typically between 50 nm and 500 nm, but they can be even larger, measuring 1–10 μm. The ISEV recommends the use of appropriate nomenclature for EVs, classifying them by clear, measurable characteristics (such as cell of origin, molecular markers, size, etc.) thus abandoning terms such as “exosomes” or “microvesicles” that were previously used [23][36][37].
EVs are present in many biological fluids, including blood, CSF, urine, saliva, and amniotic fluid, as well as in the conditioned medium of cell culture [38][39]. Their role was originally thought to be a source of cellular dumping; however, it has since been found that EVs play important roles in participating in cell-to-cell communication via the transfer of membrane receptors, proteins, lipids, and RNAs between cells and also in cell maintenance and tumor progression [40][41]. The function of small EVs depends on their ability to interact with recipient cells and to deliver their contents to such cells [42].
Thanks to their small size, which allows them to pass the blood–brain barrier (BBB) and deliver their cargo (biological or pharmacological) to the brain, they become a powerful therapeutic application tool in neurodegenerative diseases where the BBB represents the main obstacle to reach the injured area of CNS.

2. EVs from MSCs

It has been shown that MSC secreted factors are able not only to improve the surrounding environment of the target tissue, but also to exert beneficial effects even in the distal sites, supporting the paracrine hypothesis rather than the local transdifferentiation one [43][44]. The paracrine effects of MSCs were first described in 2006 and took into account the entire secretome released by MSCs, which contains a soluble fraction (mostly growth factors and cytokines) and a vesicular component, EVs, which transfer proteins, lipids, and genetic material to recipient cells [45][46].
MSCs are considered prolific producers of EVs compared to other types of cells [47][48] and the therapeutic use of their vesicular counterpart shows significant advantages over using parental cells, thanks to a high safety profile, low immunogenicity, and tumorgenicity [49]. The composition of MSC-derived EVs, like EVs from other sources, includes a cargo of nucleic acids, proteins, and lipids reported in several studies and in databases such as VESICLIPEDIA (http://microvesicles.org/) [50] or EXOCARTA (www.exocarta.org) [51] both accessed on 25 January 2023, a curated compendium of molecular data. The phenotype, number, and function of MSC-EVs may vary depending on the source of MSCs [52][53]. Thanks to their small size, MSC-EVs are able to migrate efficiently to the target organ after infusion, without getting trapped in pulmonary capillaries [54], crossing the BBB, and reaching the injured area in the brain. These characteristics make MSC-EVs a promising tool for a cell-free therapy in neurodegenerative diseases.

3. Therapeutic Potential of MSC-EVs in Neurodegenerative Disorders

Neurodegenerative diseases are a heterogeneous group of disorders that affect approximately 30 million individuals worldwide with distinct morphological and pathophysiological features. These diseases have a complex multifactorial etiology whose pathogenic mechanisms are currently not fully understood [55][56]. The pathological conditions arise from slow progressive and irreversible dysfunctions caused by loss of both neurons and synapses in selected areas of the nervous system. A combination of genetic and environmental factors may play a role in causing neurodegenerative diseases [57]. The incidence of neurological disorders becomes more widespread with the aging of the population [58] and results to be closely related to lifestyle factors. Likewise, environmental factors are recognized among the causes of disease and progression, and include chronic exposure to heavy metals, pesticides, and air pollutants [59][60].
Although neurodegenerative diseases present distinct characteristics, common pathways have been identified, through which the neurodegeneration proceeds. Common pathogenic mechanisms underlying many neurodegenerative diseases include abnormal accumulation of insoluble protein aggregates and misfolding [61], oxidative stress and formation of reactive oxygen species (ROS) [62], mitochondrial dysfunctions [63], and neuroinflammatory processes [64], suggesting that neurodegenerative diseases with distinct etiologies may share common pathogenic pathways [65].
Currently, no neurodegenerative disease is curable, and the available treatments only manage the symptoms or delay the progression of the disease [3].
A large number of neurodegenerative disorders are characterized neuropathologically by intracellular and/or extracellular aggregates of proteinaceous fibrils which are implicated in progressive brain degeneration [66]. For instance, the accumulation of amyloid beta (Aβ) together with the presence of neurofibrillary tangles, synapses, and neuronal loss, correlates with a progressive and gradual decline in cognitive functions, typical of Alzheimer disease (AD) [67]. Several therapeutic approaches have attempted to reduce the Aβ burden in AD patients and in transgenic mouse models: the presence of high levels of Aβ-degrading enzymes in adipose MSC-derived EVs has been considered a useful strategy to regulate the level of Aβ accumulation in the brain [68]. Indeed, EVs isolated from human umbilical cord-derived MSCs significantly enhance the expression of Aβ-degrading enzymes such as neprilysin (NEP) and insulin degrading enzyme (IEP), reducing Aβ deposition of AD in transgenic APP/PS1 mice, with a subsequent reduction in neuroinflammation and cognitive improvement [69]. Moreover, the content of antioxidant enzymes, such as the catalase in MSC-EVs, protects hippocampal neurons from oxidative stress and synaptic damage [70].
The use of MSC-EVs has been reported to act against neuronal damage and synaptic dysfunction [71], pathological signs that generally appear in the initial phase of AD, which are directly related to cognitive impairment. In this context, MSC-EVs have been shown to promote neuroprotection [72] and stimulate neurogenesis [73].
A similar scenario is envisaged with Parkinson’s disease (PD), the second most common chronic neurodegenerative disease in the world [74], characterized by the degeneration of dopaminergic neurons with the accumulation of protein aggregates of α-synuclein in the intraneuronal structure, and a consequent deficiency of dopamine production in several networks [75]. The use of MSC-EVs as a therapeutic strategy turns out to be promising, although still at an early stage. The use of the secretome from MSCs showed, in PD rat models, an improvement in motor performance outcomes [76][77]. MSC-EVs from different sources were able to promote neuroprotection of 6-hydroxy-dopamine (6-OHDA) dopaminergic neurons from oxidative stress [78], reducing substantia nigra dopaminergic neuron loss, apoptosis, and upregulating the dopamine levels in the striatum [79].
The considerable capabilities of MSC-EVs have been observed in other settings: EVs derived from adipose mesenchymal stem cells (ASCs) showed the ability to promote remyelination after injury and neuroprotection of neurons and motor neuron-like cells, after peroxide treatment in vitro [80][81], demonstrating their potential therapeutic application in several neurodegenerative diseases. In particular, motoneurons (MNs) represent the principal target of amyotrophic lateral sclerosis (ALS), due to the selective dysfunction and damage of upper and lower MNs leading to progressive paralysis and death [82]. ASC-EVs have demonstrated the ability to regulate the aggregation of the pathological SOD1 protein restoring the levels of mitochondrial proteins in neurons from G93A mutated ALS mice [83] and in MN cultures, an effect that is due to their antiapoptotic ability [84]. MN and neuromuscular junction protection, together with an improvement in motor performance was observed in SOD1(G93A) mice after repeated administration of ASC-EVs [85].
As previously reported, the regulation of ROS production plays an important role among the pathogenic mechanisms of neurodegenerative diseases. With regard to this, recently, the role of MSC-EVs in reducing oxidative and nitrosative damage has drawn much attention. Antioxidant effects have been observed in models of PD [86] and in alcohol-related brain damage [87], having effects on several cell types including neurons and glial cells [86], as well as effects reported on brain ischemic injury [88]. This evidence suggests a potential mechanism of action of MSC-EVs to counteract ROS-related damage that causes neurodegeneration. The ability to act against mitochondrial dysfunction is also reported to be a mechanism of action to counteract neurodegeneration [84][89], as well as the capacity of MSC-EVs to counteract the accumulation of aberrant proteins as previously described for Aβ accumulation in AD and α-synuclein aggregation in PD. Furthermore, MSC-EVs are able to act as modulators of the inflammatory component, whose role in the progression of neurodegenerative diseases is currently being re-evaluated.
Inflammation associated with chronic neurodegenerative diseases is not typically the trigger itself of such diseases; however, it contributes and sustains their progress due to the contribution of activated microglia and astrocytes in neuronal dysfunction and death [64]. MSC-EVs elicited a strong anti-inflammatory effect in an AD mouse model, improving the amount of M2-polarized macrophages. A reduction in inducible nitric oxide synthase (iNOS) was observed in ALS mice after MSC-EVs injection [71]. For a more extensive and complete discussion of the mechanisms of action of MSC-EVs refer to Yari et al. [33].
In light of this promising evidence, the use of MSC-EVs in the treatment of neurodegenerative diseases currently appears to be a possible innovative strategy for the treatment of incurable diseases.

4. Translational Applications of MSC-EVs in Patients with Neurodegenerative Diseases

Delivering therapeutic agents efficiently within the CNS represents one of the crucial issues of the therapies for neurodegenerative disorders. The passage through the BBB represents one of the limiting factors in conveying an efficient concentration of therapy in the areas of lesion in the CNS. The latter concern, related to cellular therapies, is strictly linked to the homing and biodistribution of transplanted cells and their vesicular counterpart, as well as to the identification of an efficient method of administration.

Preclinical data on EVs-based therapies, as previously discussed, are very encouraging: MSC-EV therapies proved to be much safer and more versatile than cell therapy, despite few clinical results being yet available [148,149]. Several studies involving the use of EVs/exosomes are registered on https://beta.clinicaltrials.gov. The majority of those are observational studies focusing on EVs from patient body fluids for diagnostic and prognostic purposes. Promising results have been confirmed in other diseases [150]. Worthy of mention is the clinical trial NCT03384433, which evaluated the stereotaxic injection of MSC-EVs overexpressing miR-124 for the treatment of ischemic stroke and its recurrence. Currently, only two trials including MSC-EVs and chronic neurodegenerative diseases are registered: depression, anxiety, and dementias (NCT04202770) and Alzheimer’s disease (NCT04388982). In NCT04202770 focused ultrasound was used to enhance the intravenous delivery of EVs from MSCs to the subgenual target for patients with refractory depression, the amygdala for patients with anxiety, and the hippocampus for patients with cognitive impairment. The registered study NCT04388982 evaluates the safety and efficacy of MSC-EVs in patients with mild to moderate dementia by repeated intranasal administration of MSC-EVs (at low, medium and high doses) twice a week, respectively, for 12 weeks. Although there are still few clinical studies currently registered, the interest in these therapies appears to be growing and corroborated by the promising results obtained from preclinical studies.

5. Conclusions

In summary, the reported studies represent the proof of concept of the potential of MSC-EVs as a therapeutic opportunity to treat neurodegenerative diseases. The possibility of combining the intrinsic properties of their parental cells with bioengineering modifications could represent a potential improvement for their clinical use. The development of a formulation of EVs that improves their biodistribution and retention in the lesion sites through an appropriate route of administration holds great promise for a facilitated delivery, mainly for CNS diseases. In this regard, the intranasal administration of MSC-EVs represents a flexible treatment, which simplifies the delivery procedure in a direct, efficient way.

Although there are still many challenges to be addressed, the clinical translation of MSC-EVs towards a real therapy represents an interesting frontier for the treatment of neurodegenerative diseases. In recent years the number of ongoing clinical trials that are actively recruiting patients has been constantly expanding and the successful translation of EV-based therapeutics in the clinic seems to be more realistic and not so distant, thanks to the rapid advances of nanotechnologies and the support of coordinated studies worldwide.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24032917

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