MSCs derived extracellular vesicles as a therapeutic paragon for neurodegenerative disorders: A viewpoint


1Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
2Jawaharlal Nehru Medical College, Karnataka, India
*Address correspondence to: Sujata Mohanty, drmohantysujata@gmail.com
Received: 05 August 2021; Accepted: 08 October 2021

Abstract: Neurodegenerative disorders are a vicious woe to the public health and wellness. Uncertainty in their underlying causes, lack of effective biomarkers for their early detection, existence of only supportive therapy, and their ever rising incidence creates an unmatched need for targeted therapies. Mesenchymal Stem Cells (MSCs) have found to be promising candidates for regenerative and remedial therapy in neurodegenerative disorders, however several biological risks and practical issues impede in their translational utility. Deriving from MSCs are certain Extracellular Vesicles (EVs), which aid in the paracrine action of MSCs and have lately gained the scientific interest for their implacability in diverse set ups. Their cargo is of utmost importance and is being explored in various different diseases like heart diseases, neuronal diseases, respiratory diseases and hepatic diseases. They thereby hold the position of a likely prospective remedial candidate for therapy against neurodegenerative disorders.

Keywords: Mesenchymal stem cells; Extracellular vesicles; Neurodegenerative disorders; Cell-free therapy; Regeneration

AD:Alzheimer’s diseases
ALS:Amyotrophic lateral sclerosis
BBB:Blood brain barrier
CDK5:Cell division protein kinase
EV:Extracellular vesicles
MS:Multiple sclerosis
MSC:Mesenchymal stem cells
NLRP3:NAcht Leucine-rich repeat Protein 3
PD:Parkinson’s disease
UC:Umbilical cord


Neurodegenerative disorders cause a grave health menace and affect millions of people around the globe. The most common ailments in this spectrum of diseases include Alzheimer’s diseases (AD), Parkinson’s disease (PD), Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Prion diseases, and Huntington’s disease (Fayazi et al., 2021). These diseases aggravate the day-to-day activities of the affected individuals, thereby deteriorating their standard of life and wellbeing. Cause of these diseases can be genetic or developmental. Some common causes include misfolding of proteins and their aggregates, neuroinflammation, generation of excessive reactive oxygen species, impaired mitochondrial function, exposure to toxic metals like lead, manganese, arsenic, and lifestyle factors (Shariati et al., 2020). Alzheimer’s and Parkinson’s disease are the most commonly affecting maladies. As per the recent reports it is suggested that about 6.2 million people in America could be suffering from Alzheimer’s disease and about 1.2 million people could develop Parkinson’s disease by 2030 (https://www.parkinson.org/Understanding-Parkinsons/Statistics; https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf).

The morbific elements of these diseases are multifarious and the pathogenesis is unclear. Moreover, the absence of any reliable biomarkers poses a great challenge to the early detection of these diseases. As a result, there is unavailability of any definitive cure (Vilaça-Faria et al., 2019). Furthermore, due to unsolicited side effects of pharmaceutical based medications, the remedial approaches against these disorders become limited for now. Therefore, the focus of therapeutics has recently shifted towards stem cell therapy (Vilaça-Faria et al., 2019). The most popular stem cell types considered for cell therapy include Embryonic Stem Cells, induced Pluripotent Stem Cells, and Adult Multipotent Stem Cells, like Mesenchymal Stem Cells (MSCs). Due to the complex ethical concerns intervening in the use of the former, MSCs and their derivatives are now gaining the spotlight (Panda et al., 2021). MSCs are adult multipotent stem cells that can be derived from various sources for instance Bone Marrow, Wharton’s Jelly, Adipose Tissue and Dental pulp (Singh et al., 2017). They possess strong differentiation capabilities and regenerative abilities, making them a compelling candidate for therapy against neurodegenerative disorders (Yao et al., 2020; Singh et al., 2020). Despite their immeasurable regenerative potential, they are still unable to be brought forward in the mainstream therapeutics due to several concerns with their transplantation. There have been several reports which suggest that MSCs, due to their large size and when administered in higher and repetitive doses for a substantial effect, are prone to causing emboli which can set off major bodily perils (Sharma et al., 2021). Furthermore their viability is questionable which impedes in a sustained effect. Above that, the chief hindrance in using whole cells for therapy against neurodegenerative disorders is that these approaches require crossing of the blood-brain barrier (BBB), which is impervious to large molecules with size more than 400 Da (Fayazi et al., 2021). In this context, the secretome of MSCs serve as an attractive contender for regenerative therapy against neurodegenerative disorders over their parent cells itself (Guy and Offen, 2020). MSCs, apart from differentiation, act through paracrine mechanisms i.e., by the release of soluble factors directly in their extracellular locale, and by the secretion of small membrane bound vesicles consisting bioactive molecules known as Extracellular Vesicles. These EVs have recently gathered the limelight and strong scientific interest of the researchers due to their small size aiding flexibility, and fascinatingly intricate cargo landscape (Gupta et al., 2021). EVs can be classified into 3 broad categories including exosomes, microvesicles and apoptotic bodies, and could be characterized based upon their size, morphology and functionality (Willms et al., 2018). Their functionality is aided by the cargo that they ferry.

The cargo of MSC derived EVs contain assorted molecules like mRNAs, miRNA, proteins, enzymes and many more which can potentially cause epigenetic manipulations. Of the EVs cargo, miRNAs have recently gained popularity as they have been found to cause epigenetic modulations via translational silencing and mRNA destabilization (Qing et al., 2018). Their horizontal transfer of cargo via the means of EVs serves as a mechanism of genetic expression regulation which could be beneficial for neuronal regeneration and neuroprotection, mainly by suppression of neuroinflammation. This horizontal transfer could involve the transfer of miRNAs, siRNAs, mRNAs, proteins for respective epigenetic modulations as discussed above. MSCs and the EVs derived from them are widely known for their anti-inflammatory potential which can hold significance for reduction in neuroinflammation, which is one of the major underlying cause and phenomena in neurodegenerative disorders (Long et al., 2017; Thomi et al., 2019). For instance, miR-188-3p in MSCs EVs has been found to suppress autophagy, neuroinflammation and apoptosis by targeting CDK5 and NLRP3 and thereby exerting a neuroprotective and regenerative effect (Li et al., 2021). Lee et al. (2014) showed that MSCs-EVs were found to transfer miR124 and miR145 which exerted regenerative and differentiation influence on astrocytes and human neuroprotective cells. Furthermore, Stem cells EV contains of miRs including miR-1000, miR-133b, miR-21, miR-34a, and miR-219 which are found to possess neuroprotective activities, like enhancing neural plasticity (Xin et al., 2013), suppression of apoptosis (Ma et al., 2013; Vallabhaneni et al., 2015), and promotion of myelination (Pusic and Kraig, 2014). Gao et al. (2020) showed that MSC-EVs were able to rescue neurons and promote their survival via the transfer of miR-21. Also, upon hypoxic exposure to MSCs, it was found that the EVs derived from them were able to promote cerebral angiogenesis (Gregorius et al., 2021). miR-106b carried by the MSC-EVs was suggested to enhance neuronal autophagy and it was also found to be a regulator and inhibitor of CDKN2B, thereby preventing neuronal apopotosis in Parkinson’s disease (Bai et al., 2021). Furthermore, the presence of membrane metallo-endopeptidases like neprilysin in MSCs-EVs help in cleavage of beta amyloid peptides, the accumulation of which is a pathological aspect in Alzheimer’s Disease (Fayazi et al., 2021; Vilaça-Faria et al., 2019; Cone et al., 2021). We would also like to highlight that these EVs also have a potent anti-oxidant property which may be exploited to combat the oxidative stress caused post seizures (Luo et al., 2021). However it is necessary that the concentration of administration of EVs and the dosage repetitions be a point of consideration during therapy.

Certain studies have suggested that EVs are found to be involved in mitochondrial transfer as a rescue mechanism (Paliwal et al., 2018). This could have a role in neurodegenerative diseases wherein mitochondrial function is impaired. Such studies evidence the biological potential and remedial action of MSCs-EVs as a therapeutic agent in neurodegenerative disorders wherein they could be recognized for both regenerative and diseases progression inhibiting actions (Silva et al., 2020; Peruzzotti-Jametti et al., 2021).

The strategy of using MSCs-EVs as a therapeutic agent is strongly promoted in our viewpoint due to the many advantages of EVs over their parent cells such as their nano-size which makes them safer to administer thereby negating the risk of embolism which persists upon whole cell transplantation (Sharma et al., 2021; Upadhya and Shetty, 2019; Upadhya and Shetty, 2021). Also, this helps them in crossing physiological barriers, for instance, the Blood Brain barrier easily (Sharma et al., 2021). Their viability and stability is unquestionable unlike their parent cells. Further, whereas MSCs have been found to get entrapped in the lung vasculature upon transplantation, they have a remote and far reaching effect (Sharma et al., 2021).

EVs can also be modified to enhance their functionality. This can be done by the aid of biotechnological and bioengineering techniques which can, for example, be used to modify their surface markers for a targeted delivery. Additionally, their vesicular membrane bound structure can be utilized for encapsulation of drugs in order to employ them as a drug delivery vehicle (Panda et al., 2021). However this field requires extensive research and an ADME database as suggested by Baek et al. (2019), should be established.

Despite their many advantages, MSC derived EVs are still in their nascent stages of therapeutic developments due to many hurdles, for instance, ambiguity in their cargo relative to the tissue specific differences of MSCs from various tissue sources (Shariati et al., 2020). This serves as a major point of consideration that due to the heterogeneity in their sources, MSC-EVs could possess differential molecular profile and functionality. The most popular MSCs sources to be used in clinical trials include Bone Marrow, Adipose Tissue and Umbilical Cord derived MSCs. In our viewpoint, we would like to suggest that Umbilical cord derived MSCs (UC-MSCs) could have an upper hand over the other tissue sources as they derive from an immunologically benefited site, and are naïve in terms of exposure to circumstantial stressors (Sharma et al., 2021). UC-MSCs are also found to be immunologically more potent and better in terms of immunomodulation, which promotes their use against neurodegenerative disorders, as brain inflammation and neuroinflammation are one of their characteristic pathophysiological features (Sharma et al., 2021; Rawat et al., 2018). In addition, the cargo profiling needs to be standardized upon different passage numbers as well. Furthermore the various types of EVs and their inherent differences need to be characterized as well. The large scale production and isolation of the EVs also pose a major challenge but is of utmost importance in order to ensure that it meets the need of the hour (Adlerz et al., 2020; Yuan et al., 2021).

In conclusion, we can suggest that even though the use of MSC-EVs is an attractive strategy for remedial approaches against neurodegenerative disorders, such in-depth standardization studies are the need of the hour to bring them forward as the key therapeutic envoy for treatment in neurodegenerative disorders.

Authors’ Contribution: The authors confirm contribution to the paper as follows: YS contributed to conceptualization and writing. SR contributed to writing and critical evaluation of the manuscript. SM contributed to conceptualization, critical evaluation, and coordinated throughout the manuscript writing. All authors approved the final version of the manuscript.

Funding Statement: The authors received no specific funding for this study.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.


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