Neuroprotective effect of mesenchymal stem cells in neurodegenerative disease : focusing on Parkinsonian disease

Abstract

"Mesenchymal stem cells (MSCs) are themselves capable of multi-potency, with differentiation under appropriate conditions into chondrocytes, skeletal myocytes, and neurons. MSCs have been also known to pose neuroprotective effects through secreting various cytotrophic factors. Based on our previous studies demonstrating neuroprotective effect of hMSCs in Parkinson’s disease, we extended our investigations into other parkinsonian disease in addition to properties of hMSCs on blood-brain barrier. .

PART A. Human mesenchymal stem cells exerts neuroprotection in an animal model of double lesion-induced multiple system atrophy-parkinsonism (MSA-P).

PART B. Inhibition of blood brain barrier (BBB) permeability by hMSCs.

First, the double lesion-induced MSA-P was established with co-injections of MPTP (10mg/day, total dose 90 mg/kg for 9 days) and 3- NP (total dose 450 mg/kg for 9 days, 12hr interval). At one day after last injection, hMSCs were injected into the tail vain (1X106cells/ml). Three groups of mice were compared (control group, only MPTP+3-NP group, hMSC treatment in MPTP+3-NP group) through histopathological and behavioral analysis. Compared to only MPTP+3-NP-treated mice, hMSCs treatment in double lesion mice significantly increased survival of TH- and NeuN-immunoreactive cells in the substantia nigra and the striatum, respectively. Additionally, hMSC treatment significantly decreased Iba-1, GFAP and increased Calbindine immunoreactive cells in the substantia nigra and the striatum. Behavioral analysis showed that the decent times on the top of a vertical wooden pole was significantly decreased in hMSCs-treated double lesion mice, comparable to controls. This study demonstrates that hMSCs treatment had a protective effect on loss of neurons in the substantia nigra and the striatum induced by MPTP+3-NP through a variety of mechanisms, such as anti-inflammatory actions, anti-apoptotic effect.

Second, the neuroinflammation plays collectively suggest that excessive neutrophil infiltration and environmental factors, such as lower astrocyte density and higher BBB permeability, contribute to severe inflammation and neuronal death in the SNpc. At 4hour (4hr) after LPS injection, hMSCs were injected into the tail vain (1X106cells/ml) and three groups of rat were compared (control group, only LPS group, hMSC treatment in LPS group) through histopathological analysis after 12hr. Compared to only LPS-treated rats, hMSCs treatment in LPS-treated rats significantly showed increase of EBA-immunoreactive cells and reduction of Evans blue- immunoreactive cells in the substantia nigra. Interestingly, Compared to only LPS-treated rats, hMSCs treatment in LPS-treated rats significantly showed increase of the densities of astrocytes, assumed to significantly influence neurovascular structure and integrity and reduction of p-gp-immunoreactive cells, the one BBB transporter. Consequently, hMSC treatment significantly showed reduction of MPO-immunoreactive cells and increase of TH-immunoreactive cells in the substantia nigra. This study demonstrates that hMSCs treatment had a protective effect on neuroinflammation plays in the substantia nigra induced by LPS through inhibition of BBB permeability

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