Comparative effects of human umbilical cord-derived mesenchymal stromal cells and their extracellular vesicles in a mouse model of parkinsonism

Numerous studies have demonstrated the therapeutic potential of multipotent mesenchymal stromal cells (MMSCs) in neurodegenerative diseases due to their trophic properties, suppression of inflammation at the lesion site, reduction of apoptosis, and stimulation of endogenous neurogenesis via the secretion of bioactive factors. Similar to the cells from which they originate, extracellular vesicles (EVs) exert therapeutic effects, including stimulation of cell migration and extracellular matrix synthesis, as well as anti-apoptotic, immunomodulatory, and anti-inflammatory activities. Given their improved safety profile, EVs are considered a promising alternative to cell therapy for nervous system disorders. The aim of study was to compare the effects of human umbilical cord-derived MMSCs (hUC-MMSCs) and their EVs on behavioral parameters, immune cell populations, and antioxidant defense in the brains of mice with an experimental model of parkinsonism. Materials and methods. Parkinsonism was induced in 6–7 months old male 129/Sv mice by a single intraperitoneal injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 30 mg/kg (control group). To assess therapeutic efficacy, either hUC-MMSCs (5×105 cells) or EVs derived from an equivalent number of cells were administered via tail vein injection 7 days post-induction. Flow cytometry was used to determine the percentages of CD3+ T lymphocytes and CD11b+ macrophages in brain cell suspensions. Biochemical analysis of brain homogenates was performed to assess malondialdehyde (MDA) levels and the activities of antioxidant enzymes glutathione peroxidase (GP) and glutathione reductase (GR). Motor and non-motor behaviors were evaluated using the open field, rigidity, memory, and rotarod tests. Results. MPTP administration led to reduced motor, exploratory, and cognitive activity, and increased emotional reactivity compared to intact animals. An increase in brain macrophage content and MDA levels, along with a reduction in GP and GR activities, was also observed. hUC-MMSC transplantation partially restored emotional and motor functions, reduced macrophage numbers and MDA levels, and increased GP activity. However, it was associated with further suppression of some cognitive parameters, potentially related to the treatment regimen. EV administration similarly improved motor and emotional functions, but unlike hUC-MMSCs, did not impair cognitive performance. Moreover, EVs more effectively enhanced GP and GR activities and reduced brain macrophage levels compared to cell therapy. Conclusions. Both hUC-MMSCs and their EVs improve CNS function in experimental parkinsonism by reducing macrophage infiltration and oxidative stress in the brain. The more pronounced beneficial effects observed with EVs suggest they may represent a promising and safer alternative to cell-based therapies for Parkinson’s disease.