Influence of mesenchymal stem cell transplantation on stereotypic behavior and dopamine levels in rats with Tourette syndrome

Abstract

Context: Tourette syndrome (TS) is a heterogeneous neuropsychiatric disorder. Chronic motor and phonic tics are central symptoms in TS patients. For some patients, tics are intractable to any traditional treatment and cause lifelong impairment and life-threatening symptoms. New therapies should be developed to address symptoms and overt manifestations of TS. Transplantation of neurogenic stem cells might be a viable approach in TS treatment.

Objective: We used mesenchymal stem cell (MSC) transplantation to treat TS. We discuss the mechanism of action, as well as the efficiency of this approach, in treating TS.

Settings and design: An autoimmune TS animal model was adopted in the present study. Forty-eight Wistar rats were randomly allocated to the control group and the 2 experimental groups, namely, TS rats+vehicle and TS rats+MSC. MSCs were co-cultured with 5-bromodeoxyuridine (BrdU) for 24 h for labeling prior to grafting.

Methods: Stereotypic behaviors were recorded at 1, 7, 14, and 28 days after transplantation. Dopamine (DA) content in the striatum of rats in the 3 groups was measured using a high-performance liquid chromatography column equipped with an electrochemical detector (HPLC-ECD) on day 28 after transplantation.

Statistical analysis: Statistical analysis was performed by repeated measurements analysis of variance to evaluate stereotypic behavior counts at different time points.

Results: TS rats exhibited higher stereotypic behavioral counts compared with the control group. One week after transplantation, TS rats with MSC grafts exhibited significantly decreased stereotypic behavior. Rats with MSC grafts also showed reduced levels of DA in the striatum when compared with TS rats, which were exposed only to the vehicle.

Conclusions: Intrastriatal transplantation of MSCs can provide relief from the stereotypic behavior of TS. Our results indicate that this approach may have potential for developing therapies against TS. The mechanism(s) of the observed effect may be related to the suppression of DA system by decreasing the content of DA in TS rats.

Figure 1. Stereotypy counts were recorded for 30 min at different time points in 3 groups.

Scores are higher in the Tourette syndrome (TS) group than those in the control group. TS rats with mesenchymal stem cell (MSC) grafts exhibited decreased stereotypic behaviors compared with TS+vehicle rats. P<0.05.

Figure 2. Flow cytometry analysis of MSCs.

Cells were cultured for 3–4 passages, harvested, and analyzed by a flow cytometry system. The y-axis represents the number of cells, and the x-axis represents CD29, CD-44, CD105, CD106, CD34, and CD45.

Figure 3. Immunostaining analyses of grafted MSCs in a rat model of Tourette’s syndrome at 4 wk after transplantation.

Grafted MSCs are identified by BrdU staining. (A) Grafted cells are double-labeled with anti-BrdU (purple) and anti-Nestin (red). (B) Some grafted MSCs differentiated into neurons, as evidenced by double-labeling with BrdU and MAP-2. (C) Grafted cells differentiated into astrocytes, which coexpressed BrdU and GFAP. Scale bar: 20 µm. Arrows represent transplanted MSCs that differentiated into different types of neural cells.

Figure 4. The amounts of dopamine (DA) in striatum homogenate (Figure 4) were analyzed at the end of the test by high-performance liquid chromatography with electrochemical detection in 3 groups (n = 16).