Abstract
In animal models of stroke, behavioral assessments could be complemented by a variety of neuroimaging studies to correlate them with recovery and better understand mechanisms of improvement after stem cell therapy. We evaluated morphological and connectivity changes after treatment with human mesenchymal stem cells (hMSCs) in a rat stroke model, through quantitative measurement of T2-weighted images and diffusion tensor imaging (DTI). Transient middle cerebral artery occlusion rats randomly received PBS (PBS-only), FBS cultured hMSCs (FBS-hMSCs), or stroke patients’ serum cultured hMSCs (SS-hMSCs). Functional improvement was assessed using a modified neurological severity score (mNSS). Quantitative analyses of T2-weighted ischemic lesion and ventricular volume changes were performed. Brain microstructure/connectivity changes were evaluated in the ischemic recovery area by DTI-derived microstructural indices such as relative fractional anisotropy (rFA), relative axial diffusivity (rAD), and relative radial diffusivity (rRD), and relative fiber density (rFD) analyses. According to mNSS results, the SS-hMSCs group showed the most prominent functional improvement. Infarct lesion volume of the SS-hMSCs group was significantly decreased at 2 weeks when compared to the PBS-only groups, but there were no differences between the FBS-hMSCs and SS-hMSCs groups. Brain atrophy was significantly decreased in the SS-hMSCs group compared to the other groups. In DTI, rFA and rFD values were significantly higher and rRD value was significant lower in the SS-hMSCs group and these microstructure/connectivity changes were correlated with T2-weighted morphological changes. T2-weighted volume alterations (ischemic lesion and brain atrophy), and DTI microstructural indices and rFD changes, were well matched with the results of behavioral assessment. These quantitative MRI measurements could be potential outcome predictors of functional recovery after treatment with stem cells for stroke.
Highlights
Most preclinical studies show promising results for stem cell therapy in various small animal models of stroke, randomized trials of stem cell therapy in stroke patients show negative or mixed results [1,2,3,4,5,6,7,8]
We evaluated magnetic resonance imaging (MRI) measurements after intravenous injection of human mesenchymal stem cells, either naïve or preconditioned, in a rat transient middle cerebral artery occlusion stroke model
There were no significant differences in ischemic lesion volumes on day 1 among the groups (PBS-only vs. fetal bovine serum (FBS)-human mesenchymal stem cells (hMSCs), p = 0.635; PBS-only vs. SShMSCs, p = 0.916; FBS-hMSCs vs. stroke patients’ serum (SS)-hMSCs, p = 0.880)
Summary
Most preclinical studies show promising results for stem cell therapy in various small animal models of stroke, randomized trials of stem cell therapy in stroke patients show negative or mixed results [1,2,3,4,5,6,7,8]. A systematic search for reports of experiments using stem cells in animal models of stroke showed that while stem cells appear to be of some benefit in animal models of stroke, the validity of preclinical data is potentially confounded by poor study quality, lack of standards in the conducting and reporting of experiments, publication bias, and significant experimental design differences between clinical and preclinical trials [9,10,11]. Such discrepancy between preclinical and clinical studies calls for the need for objective parameters to evaluate the effects of stem cells in small animal models of stroke. Imaging-based biomarkers can be good tools to investigate the therapeutic efficacy of stem cell therapy in ischemic stroke
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