Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model

Abstract

Growing evidence has demonstrated that neurogenesis in the subventricular zone (SVZ) is significantly decreased in Parkinson's disease (PD). Modulation of endogenous neurogenesis would have a significant impact on future therapeutic strategies for neurodegenerative diseases. In the present study, we investigated the augmentative effects of human mesenchymal stem cells (hMSCs) on neurogenesis in a PD model. Neurogenesis was assessed in vitro with 1-methyl-4-phenylpyridinium (MPP(+)) treatment using neural precursor cells (NPCs) isolated from the SVZ and in vivo with a BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunochemical analyses were used to measure neurogenic activity. The number of BrdU-ir cells in the SVZ and the substantia nigra (SN) was significantly increased in the hMSC-treated PD group compared with the MPTP-only-treated group. Double-stained cells for BrdU and tyrosine hydroxylase were notably observed in the SN of hMSC-treated PD animals, and they did not colocalize with the nuclear matrix; however, double-stained cells were not detected in the SN of the MPTP-induced PD animal model. Furthermore, hMSC administration increased the expression of the epidermal growth factor receptor (EGFR) in the SVZ of PD animals, and the coculture of hMSCs significantly increased the release of EGF in the medium of MPP(+)-treated NPCs. The present study demonstrated that hMSC administration significantly augmented neurogenesis in both the SVZ and SN of PD animal models, which led to increased differentiation of NPCs into dopaminergic neurons in the SN. Additionally, hMSC-induced modulation of EGF seems to be an underlying contributor to the enhancement of neurogenesis by hMSCs. The modulation of endogenous adult neurogenesis to repair the damaged PD brain using hMSCs would have a significant impact on future strategies for PD treatment.