Neuroprotective effects of transplantation of human mesenchymal stem cells in a Parkinsonian animal model

Abstract

Parkinson''s disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta (SNc). It is one of the most common neurodegenerative diseases in the elderly population, and the patients’ number is expected to rise dramatically in the coming years. Therefore, the demand for effective therapy against PD has been greatly increased. Transplantation of stem cells may help to recover the functional deficit of PD patients by replacing damaged neurons or through other beneficial mechanisms. Mesenchymal stem cells (MSCs) are derived from the adult bone marrow. Compared to other types of stem cell, MSCs have significant advantages and greater potentials for immediate clinical applications. In the present study, neuroprotective effects of transplanted human MSCs (hMSCs) were evaluated in a parkinsonian rat model. Animal model of PD was established by injection of 6-hydroxydopamine hydrobromide (6-OHDA) into the striatum (ST). Two weeks after 6-OHDA injection cultured hMSCs were transplanted into the cistern magna and the animals were sacrificed at 1, 2, 4 and 8 weeks after the transplantation. After removal of brains, change in the expression of various pro- and anti-inflammatory cytokines, microglial activation and the level of neurotrophic factors were examined. Also, tyrosine hydroxylase (TH) immunohistochemistery, quantification of TH mRNA and TH protein as well as rotational behavior analysis were assessed. Transplantation of hMSCs resulted in a decrease in the number of activated microglia, and increase in the expression of anti-inflammatory cytokines (IL-6, IL-10, and TGF-β) as well as neurotrophic factors (BDNF, NGF, NT3 and GDNF). Compared to the sham-grafted group, relatively large number of TH-positive neurons were found in the ipsilateral SNc after hMSCs transplantation. Also, increased expressions of TH mRNA and TH protein were confirmed after the transplantation of hMSCs. Finally the hMSCs-transplanted group showed significant decrease in amphetamine-induced asymmetrical rotations, compared with those of the sham-grafted group. Taken together, the present study supports the idea that hMSCs transplantation have neuroprotective effect on the dopaminergic neurons of the SNc, probably through up-regulation of neurotrophic factors and anti-inflammatory cytokines. This neuroprotective effect was confirmed by a recovery of functional deficit which was demonstrated by the rotational behavior test. These findings imply that transplanted hMSCs might induce neural plasticity and enable the damaged brain function to recover. However, a major question regarding specific roles of hMSCs in recovery of functional deficit of the parkinsonian rat still remained to be answered. Nevertheless, this study suggests an advanced in development of PD therapeutics using hMSCs.