MSC-derived exosomes are hypoimmunogenic (due to the lack of MHC-II and low expression of MHC-I) nanocarriers that comprise various immunoregulatory components. Exosomes have several advantages, they are able to cross the blood–brain barrier and blood capillaries, and are small enough to avoid being cleared by the reticuloendothelial system [
73]. The mechanisms of cellular recognition and internalization are still unclear. Antigen recognition, adhesion, and free-floating are described as cellular recognition mechanism, while fusion, phagocytosis, micropinocytosis, and raft- and receptor-mediated endocytosis are indicated as exosomal internalization processes [
74].
Exosomes have proven effective in direct MSCs transplantation, and their positive therapeutic effects have been shown in different disease models, in particular, they were beneficial for central nervous system pathologies. In a stroke animal model, MSC-derived exosomes, intravenously administered, stimulated angiogenesis and neurogenesis, neurite remodeling, and improved animal motor performances [
75]. The same neuroprotective effect was shown in a traumatic brain injury model after MSC-derived exosomes administration; indeed, a reduction of neuroinflammation and better outcomes were reported [
76]. Spinal cord injury rats, upon MSC-derived exosomes injection, showed reduced inflammation and increased neuronal regeneration [
77,
78]. In addition, in Alzheimer’s disease, the positive effects of MSC-derived exosomes with a particular impact on neuroplasticity were reported [
79].
3. MSC-Secretome: miRNA Relevance and Theranostic Applications in PD
Secretome derived from MSCs, and in particular its miRNAs component, has also been indicated as a valuable tool for targeted therapies and diagnostics. miRNAs are a highly studied class of non-coding RNAs responsible for the regulation of different genes through RNA messenger degradation or inhibition of their translation [
82]. Numerous miRNAs have been indicated as α-synuclein modulators. For example, altered binding between and fibroblast growth factor 20 (FGF20) mRNA and miR-433 induced increased FGF20 levels, which consequently led to elevated α-synuclein protein levels in the cell [
83]. Further, high miR-16-1 levels block the translation of the HSP70 (heat shock protein 70) mRNA, involved in α-synuclein inhibition, thus leading to an accumulation of α-synuclein [
84]. Moreover, targeting miR-7, miR-153, and miR-34b/c from binding on their α-synuclein induces elevated levels of α-synuclein [
85,
86].
In PD, a relation between miR-34b/c reduction and the resultant DJ-1 and PARKIN decline in several brain areas was found [
87]. Notably, increased miR-494 and miR-4639-5p levels trigger a direct decrease of DJ-1 protein expression, making dopaminergic neurons more susceptible and predisposed to the PD phenotype [
88,
89]. Interestingly, it has been recently proposed that MSC-derived secretome can ameliorate different biomarkers of PD pathophysiology, thus suggesting MSC-derived secretome as a promising approach to identify and generate valuable PD biomarkers [
90]. As mentioned above, MSCs secrete different biomolecules and factors, including exosomes carrying miRNA, which may represent potential biomarkers but also modulators of different pathways underlying various disorders, including PD. Theranostic applications in PD exploiting the potential of MSC-derived secretome, mainly concern the targeting of the injured brain areas and delivering miRNAs through the blood-brain barrier. Thanks to the nature of exosomes, their application in the theranostic field and in clinic have received a lot of interest. Still, different points need to be addressed, such as the “best” MSCs line and the development of valid isolation techniques and loading methods without altering the exosomal component and integrity. However, MSC-derived exosomes may represent a valuable solution. In fact, numerous experiments revealed that MSC-derived exosomes are able to transfer miRNAs to neuronal cells, for instance, exosomes enriched in miR-133b can stimulate neurite outgrowth [
90,
91], one of the miRNAs generally decreased in PD. Further, miR-21 and miR-143, leading players in immune response, and neuroinflammation were also observed in MSC-derived exosomes [
92]. Interestingly, in MSC-derived exosomes, a miRNA cluster composed of miR-18a, miR-17, miR-20a, miR-19a/b, and miR-90a, involved in axonal growth, neurogenesis, neurite remodeling and in CNS (central nervous system) recovery, was detected [
93,
94].
Another theranostic application in PD exploits the human Periapical Cyst-MSCs (hPCyMSCs) differentiated in dopaminergic neurons; thus hPCyMSC-derived exosomes may be useful therapeutic carriers for PD. hPCy-MSCs exposed to a neural-inductive medium led to functional dopaminergic neurons; the exosomes isolation from the CM of these MSCs is presently standardized [
95]. The analysis of circulating exosome-derived miRNA through microarrays and gene sequencing could be related to nanotechnologies: This is a significant point to improving the capability of new smart nanomaterials to capture the small-sized biomolecules, representing a theranostic approach with elevated sensitivity and extreme specificity [
96].
On this basis, it is relevant to isolate and characterize the entire set of biomolecules released by MSCs and in particular hPCy-MSCs, and to dissect the cellular and molecular mechanisms regulated by miRNAs. These new understandings may allow for the development of new therapeutic approaches and offer novel evidence on functional biomarkers for early diagnosis and monitoring of neurodegenerative diseases, with particular attention to PD.
4. Conclusions and Future Perspectives
PD is a debilitating neurodegenerative disorder that affects millions of people worldwide; however, the molecular and cellular underlying mechanisms are still unclear. Although there are advances in the PD research field, the current therapeutic approaches improve PD patients’ quality of life, but they are not able to counteract PD progression and to stimulate dopaminergic neurons survival/differentiation. Thus, recently, MSC-derived secretome and its exosomal components have been suggested as promising therapeutic tools for numerous neurodegenerative disorders, including PD, due to their ability to promote dopaminergic neurons survival, stimulate neurogenesis, decrease neuroinflammation, promote functional recovery in in vivo models.
To date, there is no cure for PD, and thus, recently, attention has been focused on cell-free approaches. MSCs have become widely used for cell-based therapy due to less scientific and ethical issues compared to the use of other kinds of cells. The ability of MSCs to release exosomes and various trophic factors makes the use of MSCs attractive for PD treatment. Thanks to their small size and/or soluble nature, these secreted molecules can cross the blood–brain barrier; moreover, exosomes are intrinsically less risky compared to live stem cell transplants. Exosomes cannot transform into harmful or malignant cells; they cannot replicate; they are less prone to activate an immunogenic response; and a virus cannot infect them. In light of the insights reported in this review, the use of MSC-derived secretome is encouraging in PD.
Further studies are needed to identify a personalized approach for the different neurodegenerative diseases and to create a new, useful, cell-free therapeutic approach towards a robust clinical outcome for PD patients. Another point that needs to be clarified is if the encouraging results are due to one or two factors or a combination of different molecules present in the secretome. To date, it is pretty clear that MSC-derived secretome exerts positive effects on neuronal cell survival, differentiation, and proliferation; however, future studies need to characterize all the bioactive molecules fully. Thus, MSC-derived secretome or their released exosomes may be used as a potential therapeutic approach or as adjuvant therapy for PD symptoms and to counteract the disease progression. Furthermore, their secretome may be used as a vehicle in cell transplantation approaches to improve the viability and survival of engrafted cells and also as a diagnostic approach. These different aspects of the knowledge about the secretome may permit the advancement of targeted secretome to fight different pathophysiological impairments in a multidisciplinary manner. In addition, since MSC-derived secretome is able to stimulate neurotrophic (i.e., BDNF, a biomarker of the majority of neurodegenerative disorders) and neuronal survival pathways and to counteract neuronal death, it could also be beneficial against other neurodegenerative conditions, including polyglutamine disorder, Alzheimer’s disease, and stroke.