Bone Marrow Stromal Cell Transplantation Enhances Recovery of Local Glucose Metabolism After Cerebral Infarction in Rats: A Serial F-18-FDG PET Study

Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Journal of Nuclear Medicine (Impact Factor: 6.16). 11/2012; 54(1). DOI: 10.2967/jnumed.112.109017
Source: PubMed


This study aimed to assess whether (18)F-FDG PET could serially monitor the beneficial effects of bone marrow stromal cells (BMSC) on cerebral glucose metabolism when transplanted into the infarct brain of rats.

The BMSC from green fluorescent protein transgenic rats or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 d after permanent middle cerebral artery occlusion of rats. Local glucose metabolism was semiquantitatively measured at 6 and 35 d after ischemia using (18)F-FDG PET. Motor function was serially evaluated throughout the experiments. At 35 d after ischemia, immunohistochemistry was performed to evaluate the phenotype of BMSC and their effects on the expression of brain-type glucose transporters.

BMSC transplantation not only enhanced functional recovery but also promoted the recovery of glucose utilization in the periinfarct area when stereotactically transplanted at 1 wk after ischemia. The engrafted cells were widely distributed, and most expressed a neuron-specific protein, NeuN. BMSC transplantation also prevented the pathologic upregulation of glucose transporters in the periinfarct neocortex.

The present findings strongly suggest that the BMSC may enhance functional recovery by promoting the recovery of local glucose metabolism in the periinfarct area when directly transplanted into the infarct brain at clinically relevant timing. The BMSC also inhibit the pathologic upregulation of brain-isoform glucose transporters type 1 and 3. (18)F-FDG PET may be a valuable modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situations.

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    • "In our study, the density of GLUT1 is markedly higher in the peri-infarct regions of the IRU group rats than the Sham group rats, suggesting the self-adaptation to ensure the glucose delivery to the tissue to protect the brain. However, the DHI treatment significantly suppressed its upregulation by improving glucose utilization in the peri-infarct regions, and a similar result was achieved by Miyamoto et al. [45]. However, the underlying mechanisms through which the DHI treatment suppresses the upregulation of GLUT1 is unclear, and further studies are necessary to elucidate this issue. "
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    ABSTRACT: This study aimed to investigate neuroprotection of Danhong injection (DHI) in a rat model of cerebral ischemia using (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). Method. Rats were divided into 5 groups: sham group, ischemia-reperfusion untreated (IRU) group, DHI-1 group (DHI 1 mL/kg/d), DHI-2 group (DHI 2 mL/kg/d), and DHI-4 group (DHI 4 mL/kg/d). AII the treated groups were intraperitoneally injected with DHI daily for 14 days. The therapeutic effects in terms of cerebral infarct volume, neurological function, and cerebral glucose metabolism were evaluated. Expression of TNF-α and IL-1β was detected with enzyme-linked immunosorbent assay (ELISA). Levels of mature neuronal marker (NeuN), glial marker (GFAP), vascular density factor (vWF), and glucose transporter 1 (GLUT1) were assessed by immunohistochemistry. Results. Compared with the IRU group, rats treated with DHI showed dose dependent reductions in cerebral infarct volume and levels of proinflammatory cytokines, improvement of neurological function, and recovery of cerebral glucose metabolism. Meanwhile, the significantly increased numbers of neurons, gliocytes, and vessels and the recovery of glucose utilization were found in the peri-infarct region after DHI treatment using immunohistochemical analysis. Conclusion. This study demonstrated the metabolic recovery after DHI treatment by micro-PET imaging with (18)F-FDG and the neuroprotective effects of DHI in a rat model of cerebral ischemic-reperfusion injury.
    Evidence-based Complementary and Alternative Medicine 02/2014; 2014:430757. DOI:10.1155/2014/430757 · 1.88 Impact Factor
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    • "Rat models of ischemia have used FDG-PET to detect metabolic variations as markers of predicting tissue fate or recoverability (Fu et al., 2009; Walberer et al., 2012) and have shown FDG-PET to be more sensitive to metabolic alterations in the ischemic core at earlier time points post-injury (Sobrado et al., 2011). FDG-PET has also been useful for tracking novel treatment outcomes of ischemia, as demonstrated by recent work with transplantation of bone marrow stromal cells for improvement in cerebral glucose metabolism (Miyamoto et al., 2013). These studies demonstrate a potential for this modality to be used in determination of spread of an injury with time as well as for discriminating viable tissue from injured for therapeutic targeting. "
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    ABSTRACT: Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States and is a contributing factor to one third of all injury related deaths annually. According to the CDC, approximately 75% of all reported TBIs are concussions or considered mild in form, although the number of unreported mild TBIs (mTBI) and patients not seeking medical attention is unknown. Currently, classification of mTBI or concussion is a clinical assessment since diagnostic imaging is typically inconclusive due to subtle, obscure, or absent changes in anatomical or physiological parameters measured using standard magnetic resonance (MR) or computed tomography (CT) imaging protocols. Molecular imaging techniques that examine functional processes within the brain, such as measurement of glucose uptake and metabolism using [(18)F]fluorodeoxyglucose and positron emission tomography (FDG-PET), have the ability to detect changes after mTBI. Recent technological improvements in the resolution of PET systems, the integration of PET with magnetic resonance imaging (MRI), and the availability of normal healthy human databases and commercial image analysis software contribute to the growing use of molecular imaging in basic science research and advances in clinical imaging. This review will discuss the technological considerations and limitations of FDG-PET, including differentiation between glucose uptake and glucose metabolism and the significance of these measurements. In addition, the current state of FDG-PET imaging in assessing mTBI in clinical and preclinical research will be considered. Finally, this review will provide insight into potential critical data elements and recommended standardization to improve the application of FDG-PET to mTBI research and clinical practice.
    Frontiers in Neuroenergetics 01/2014; 5:13. DOI:10.3389/fnene.2013.00013
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    • "Although the brain is thought to be immune-privileged, it is likely that BMSCs were eliminated via immune rejection mechanisms [32]. Interestingly, recent studies using GFP-labeled BMSCs injected directly into brain parenchyma contrastingly found labeled cells in the brain many weeks after transplantation [33], [34], suggesting that the absence of BMSCs in the brain in our study may be initiated by rejection-related mechanisms in the periphery. "
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    ABSTRACT: In this study, rat bone marrow stromal stem cells (BMSCs) were tracked after IV administration to rats with experimental stroke caused by middle cerebral artery occlusion (MCAO). In addition, the effects of BMSC treatment on blood cell composition, brain glia and sensorimotor behavior was studied and compared to that which occurred spontaneously during the normal recovery process after stroke. We found that the vast majority of radiolabeled or fluorescently labeled BMSCs traveled to and remained in peripheral organs (lungs, spleen, liver) 3 days after IV injection in the MCAO rat. Once in the circulation, BMSCs also produced rapid alterations in host blood cell composition, increasing both neutrophil and total white blood cell count by 6 hours post-injection. In contrast, few injected BMSCs traveled to the brain and almost none endured there long term. Nonetheless, BMSC treatment produced dramatic changes in the number and activation of brain astroglia and microglia, particularly in the region of the infarct. These cellular changes were correlated with a marked improvement in performance on tests of sensory and motor function as compared to the partial recovery of function seen in PBS-injected control rats. We conclude that the notable recovery in function observed after systemic administration of BMSCs to MCAO rats is likely due to the cellular changes in blood and/or brain cell number, activation state and their cytokine/growth factor products.
    PLoS ONE 03/2013; 8(3):e60049. DOI:10.1371/journal.pone.0060049 · 3.23 Impact Factor
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