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, 9 (1), 5674

Safety and Efficacy of Intraventricular Delivery of Bone Marrow-Derived Mesenchymal Stem Cells in Hemorrhagic Stroke Model

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Safety and Efficacy of Intraventricular Delivery of Bone Marrow-Derived Mesenchymal Stem Cells in Hemorrhagic Stroke Model

Peng Huang et al. Sci Rep.

Abstract

External ventricular drain (EVD) is used clinically to relieve intracranial pressure and occasionally to deliver medications following intracerebral hemorrhage (ICH). Mesenchymal stem cell (MSC) therapy has been shown to be neuroprotective and can induce neuroregeneration in stroke models. We evaluated the safety and efficacy of delivering MSCs intraventricularly in a rat hemorrhagic stroke model. Using autologous blood, hemorrhagic stroke was induced at specific coordinates in the right basal ganglia. After 30 minutes, rats were treated with either bone marrow-derived MSCs or a phosphate-buffered saline placebo via direct intraventricular infusion. Three dosages (2 × 105/kg, 5 × 105/kg, and 1 × 106/kg) of MSCs were administered. Forelimb use asymmetry test was employed to evaluate functional improvement after cell therapy. At the end of the experiment, peripheral blood samples and organs were harvested; biochemistry, cytokine, and growth factor analysis and histology evaluations were performed to explore cell toxicity and cell fate, and the effects of MSC therapy on injury volume, anti-inflammation, and neurogenesis. Intraventricular administration of MSCs in ICH rat model showed improved behavior and alleviated brain damage. Additionally, treated ICH rats showed significantly reduced expression of IL-1α, IL-6, and IFN-γ. No obvious cell toxicity was noticed through blood chemistry and histology evaluation. None of the infused MSCs were detected at the end of the experiment. EVD is safe and effective to use as a method of delivering MSCs to treat ICH. Intraventricularly delivered MSCs have anti-inflammatory properties and a capacity to induce neurogenesis and improve function following ICH injury.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Rat Experimental Design. ICH surgery was performed on Day (D) 0. Twenty-four hours later, MSCs were intraventricularly infused. Starting from D3, rat behavior was assessed using forelimb use asymmetry test (cylinder test), performed at all time points (indicated by arrows). Blood samples and main organs were collected at D21 for further analysis.
Figure 2
Figure 2
Intraventricular Administration of MSCs is feasible and safe. (A) Consecutive rat weight monitoring throughout the experiment showed no mean weight changes for 3 weeks. (B) Weight comparison of organs at the end of the experiment among all groups showed no notable changes in the mean rat organ weight. (C) Mean serum ALT, glucose and creatinine was not notably different among the rat groups compared with control group. ALT indicates alanine aminotransferase; SGPT, serum glutamic pyruvic transaminase.
Figure 3
Figure 3
Brain Coronal Sections. Hematoxylin and eosin staining (A) and injury volume calculation (B) after intraventricular administration of MSCs were shown. Three weeks after infusion of 100 µL autologous blood, the damaged area was measured by ImageScope software. Means and standard deviations of the injury size were determined. The area significantly decreased in the 2 × 105/kg and 1 × 106/kg MSC-treated groups compared to the untreated ICH group. *Indicates P < 0.05 compared to ICH group.
Figure 4
Figure 4
Intraventricular administration of MSCs Enhances Doublecortin Expression in Subventricular and Boundary Zones of the brain injury site. Several (>10) brain sections from each animal in each dose group were prepared. The figure represents the best section with the most evidence of neurogenesis from each group. (A) Representative image from control group with no ICH and MSC or PBS infusion. (E) Representative image from ICH control group that only received PBS. (BD) Images from rats receiving ICH surgery with different dose of MSC infusion. Scale bar: 3 mm.
Figure 5
Figure 5
MSC Decreased Inflammatory Response in ICH Rat Model. Rat Cytokine Array/Chemokine Array 27 Plex (RD27) Assay was performed on rat serum samples collected 21 days after intraventricular administration of MSCs. We saw significant reduction of proinflammatory cytokines IL-1α, IL-6 and IFNγ. *Indicates P < 0.05 compared to ICH group.
Figure 6
Figure 6
Behavior Analysis with Forelimb Use Asymmetry Test. (A) 3 days; (B) 7 days; (C). 14 days; and (D). 21 days after ICH surgery. Control group did not receive ICH surgery. ICH group received PBS only, while the remaining groups received different doses of intraventricularly administered MSCs. *Indicates P < 0.05 compared to ICH group.

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