MRI-guided focused ultrasound for treating Parkinson's disease with human mesenchymal stem cells

Abstract

Parkinson's disease (PD) is a progressive disorder that affects the nervous system and causes regions of the brain to deteriorate. In this study, we investigated the effects of MR-guided focused ultrasound (MRgFUS) for the delivery of human mesenchymal stem cells (MSCs) on the 6-hydroxydopamine (6-HODA)-induced PD rat model. MRgFUS-induced blood-brain barrier (BBB) permeability modulation was conducted using an acoustic controller with the targets at the striatum (ST) and SN. Human MSCs were injected immediately before sonication. Here, we show that we can deliver human MSCs into Parkinsonian rats through MRgFUS-induced BBB modulation using an acoustic controller. Stem cells were identified in the sonicated brain regions using surface markers, indicating the feasibility of MSC delivery via MRgFUS. MSCs + FUS treatment significantly improved the behavioural outcomes compared with control, FUS alone, and MSCs alone groups (p < 0.05). In the quantification analysis of the TH stain, a significant reservation of dopamine neurons was seen in the MSCs + FUS group as compared with the MSCs group (ST: p = 0.03; SN: p = 0.0005). Mesenchymal stem cell therapy may be a viable treatment option for neurodegenerative diseases such as Parkinson's. Transcranial MRgFUS serves as an efficacious and safe method for targeted and minimally invasive stem cell homing.

Keywords: 6-hydroxydopamine; MR-guided focused ultrasound; Mesenchymal stem cells; Parkinson’s disease.

Fig. 1

Focused ultrasound experimental setup.

Fig. 2

Representative blood-brain barrier (BBB) permeability modulation in Parkinson’s disease rats after Magnetic resonance imaging-guided focused ultrasound. (A) T1-weighted images post-treatment demonstrated the BBB permeability enhancement in the striatum (ST) and substantia nigra (SN) in both coronal and sagittal views, compared to pre-treatment. (B) No obvious hypo-intense signal was found in the sonicated regions in the post-sonication T2* images. (C) The BBB permeability enhancement thresholds in ST and SN using the acoustic controller.

Fig. 3

The feasibility of delivering Mesenchymal Stem Cells (MSCs) via MR-guided focused ultrasound (MRgFUS) and microbubbles is shown. MSCs were identified using stem cell markers (A) CD90 and (B) CD105, and (C) Prussian blue 2 h after sonication. The arrows indicate the positive cells.

Fig. 4

The behavioural data were collected to compare pre-treatment and the endpoint. MSCs + FUS treatment significantly improves the outcome in the cylinder and apomorphine-induced rotation tests. (A) MSCs + FUS elicited a significant improvement in the cylinder test compared to control and MSCs treatments. (B) MSCs + FUS showed a less progressive rotation response as compared to MSCs and control.

Fig. 5

Representative tyrosine hydroxylase (TH) stains shown in the striatum (ST) and substantia nigra (SN) for different treatments.

Fig. 6

FUS + MSC treatment significantly increases the ratio of TH-positive expression on the lesioned side in the (A)stratum (ST) and (B) substantia nigra (SN).

Fig. 7

Summary of experimental workflow. The injection of 6-OHDA was referred to as Day 0. The baseline and endpoint behavioural tests were performed on Day 13 and 41, respectively. The MSCs transplantation treatment using MRgFUS was conducted on Day 14. The endpoint of the study was six weeks after the 6-OHDA-induced PD surgery.