Multinuclear MRI Reveals Early Efficacy of Stem Cell Therapy in Stroke.

Compromised adult human mesenchymal stem cells (hMSC) can impair cell therapy efficacy and further reverse ischemic recovery. However, in vitro assays require extended passage to characterize cells, limiting rapid assessment for therapeutic potency. Multinuclear magnetic resonance imaging and spectroscopy (MRI/S) provides near real-time feedback on disease progression and tissue recovery. Applied to ischemic stroke, 23Na MRI evaluates treatment efficacy within 24 h after middle cerebral artery occlusion, showing recovery of sodium homeostasis and lesion reduction in specimens treated with hMSC while 1H MRS identifies reduction in lactate levels. This combined metric was confirmed by evaluating treatment groups receiving healthy or compromised hMSC versus vehicle (sham saline injection) over 21 days. Behavioral tests to assess functional recovery and cell analysis for immunomodulatory and macrophage activity to detect hMSC potency confirm MR findings. Clinically, these MR metrics may prove critical to early evaluations of therapeutic efficacy and overall stroke recovery.

Extended Ischemic Recovery After Implantation of Human Mesenchymal Stem Cell Aggregates Indicated by Sodium MRI at 21.1 T.

Extended therapeutic application remains a significant issue in the use of stem cell therapies to treat ischemic stroke. Along these lines, neurological recovery in a rodent model of ischemic stroke was evaluated following implantation of human mesenchymal stem cell aggregates (hMSC-agg), labeled with micron-sized particles of iron oxide, directly into the lateral ventricle contralateral to the ischemic lesion hemisphere. Longitudinally, disease progression and response to hMSC-agg therapy were assessed by 1H and 23Na magnetic resonance imaging (MRI) at 21.1 T to investigate cellular localization, migration, and recovery over an extended timeframe. MRI provides quantifiable metrics of tissue status through sodium distributions in addition to traditional proton imaging. Quantitative 23Na MRI revealed a significant decrease of sodium concentrations following hMSC aggregate implantation, indicating recovery of homeostasis. This result correlates positively with extended neurological recovery assessed by behavioral analysis and immunohistochemistry. These findings demonstrate the potential of implanted hMSC aggregate therapy to provide extended treatment for ischemic stroke, as well as the robustness of MRI for monitoring such approaches. This method potentially can be translated to a clinical setting for the assessment of extended cell therapy efficacy.

NODDI highlights recovery mechanisms in white and gray matter in ischemic stroke following human stem cell treatment.

PURPOSE: Diffusion MRI offers insight into ischemic stroke progression in both human and rodent models. However, diffusion MRI to evaluate therapeutic application of mesenchymal stem cells is limited. Robust analytical techniques are required to identify potential physiological changes as a function of cell therapy in stroke. Here, we seek to establish Neurite Orientation Dispersion and Density Imaging (NODDI) as a feasible method in evaluating stroke evolution in response to cell-based therapeutics. METHODS: Diffusion MRI data at 21.1T were acquired from 16 male rats. Rats were grouped randomly: naïve (baseline, N = 5), stroke with injections of phosphate buffered saline (N = 6), stroke with injection of 2D human mesenchymal stem cells (hMSC, N = 5). Data were acquired on days 1, 3, 7, and 21 post-surgery. DTI and NODDI maps were generated, with regions of interest placed in the ischemic hemisphere external capsule and striatum. Diffusion parameters were compared between groups each day, and within groups across hemispheres and longitudinally. Behavioral characterizations were on days 0 (pre-surgery), 3, 7, 14, and 21. RESULTS: The 2D hMSC preserved diffusional restriction in the external capsule compared to saline (day 1: MD, P = .4060; AD, P = .0220). NODDI indicates that hMSC may have preserved intracellular volume fractions (ICVF: day 1, P = .0086; day 3, P = .0021; day 21, P = .0383). Diffusion metrics of hMSC treated animals were comparable to naïve for the external capsule. CONCLUSIONS: NODDI compliments DTI metrics, enhances interpretation of tissue outcome in ischemic stroke following hMSC application, and may be useful in evaluating or predicting therapeutic response.

Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring.

Ischemia, which involves decreased blood flow to a region and a corresponding deprivation of oxygen and nutrients, can be induced as a consequence of stroke or heart attack. A prevalent disease that affects many individuals worldwide, ischemic stroke results in functional and cognitive impairments, as neural cells in the brain receive inadequate nourishment and encounter inflammation and various other detrimental toxic factors that lead to their death. Given the scarce treatments for this disease in the clinic such as the administration of tissue plasminogen activator, which is only effective in a limited time window after the occurrence of stroke, it will be necessary to develop new strategies to ameliorate or prevent stroke-induced brain damage. Cell-based therapies appear to be a promising solution for treating ischemic stroke and many other ischemia-associated and neurodegenerative maladies. Particularly, human mesenchymal stem cells (hMSCs) are of interest for cell transplantation in stroke, given their multipotency, accessibility, and reparative abilities. To determine the fate and survival of hMSC, which will be imperative for successful transplantation therapies, these cells may be monitored using magnetic resonance imaging and transfected with superparamagnetic iron oxide (SPIO), a contrast agent that facilitates the detection of these hMSCs. This review encompasses pertinent research and findings to reveal the effects of SPIO on hMSC functions in the context of transplantation in ischemic environments and over extended time periods. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.