Intranasal administration of mesenchymal stem cells overexpressing FGF21 demonstrates therapeutic potential in experimental Parkinson's disease.

Parkinson's disease (PD) is a prevalent movement disorder characterized by mitochondrial dysfunction and dopaminergic neuronal loss in the substantia nigra of the midbrain. Currently, there are no effective treatments to cure or slow the progression of PD, highlighting an urgent need for new therapeutic strategies. Emerging evidence suggests that mesenchymal stem cells (MSCs) and fibroblast growth factor 21 (FGF21) are potential candidates for PD treatment. This study investigates a therapeutic strategy involving FGF21 delivered via mouse MSCs in the PD model of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dopaminergic SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP). FGF21-overexpressing MSCs were administered intranasally, either before or after MPTP treatment in mice. Intranasally delivered FGF21-overexpressing MSCs efficiently migrated to the injured substantia nigra, ameliorated MPTP-induced PD-like motor deficits, reinstated dopaminergic neurons in the substantia nigra and nerve terminals in the striatum, as well as normalized brain-derived neurotrophic factor (BDNF) and FGF21 levels. In contrast, MSCs not overexpressing FGF21 showed limited or no impact on these parameters. In a PD cellular model of MPP-treated SH-SY5Y cells, FGF21-overexpressing MSCs showed enhanced PD cell viability. Treatment with conditioned medium from FGF21-overexpressing MSCs or exogenous FGF21 prevented cell death, reduced mitochondrial reactive oxygen species (ROS), and restored neuroprotective proteins, including phospho-Akt, BDNF, and Bcl-2. These findings indicate that intranasal delivery of FGF21-overexpressing MSCs holds promise as a potential PD therapy, likely through activating the Akt-BDNF-Bcl-2 pathway, normalizing mitochondrial dysfunction, and mitigating dopaminergic neurodegeneration. Further clinical investigations are essential to validate these promising findings.