Human neural stem cell transplantation into the corpus callosum of Alzheimer’s mice

The hippocampus has been the target of stem cell transplantations in preclinical studies focused on Alzheimer’s disease, with results showing improvements in histological and behavioral outcomes. The corpus callosum is another structure that is affected early in Alzheimer’s disease. Therefore, we hypothesize that this structure is a novel target for human neural stem cell transplantation in transgenic Alzheimer’s disease mouse models. This study demonstrates the feasibility of targeting the corpus callosum and identifies an effective immunosuppression regimen for transplanted neural stem cell survival. These results support further preclinical development of the corpus callosum as a therapeutic target in Alzheimer’s disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138852/1/acn3443_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138852/2/acn3443.pd

Differences in magnetic particle uptake by CNS neuroglial subclasses: implications for neural tissue engineering

AIM: To analyze magnetic particle uptake and intracellular processing by the four main non-neuronal subclasses of the CNS: oligodendrocyte precursor cells; oligodendrocytes; astrocytes; and microglia. MATERIALS & METHODS: Magnetic particle uptake and processing were studied in rat oligodendrocyte precursor cells and oligodendrocytes using fluorescence and transmission electron microscopy, and the results collated with previous data from rat microglia and astrocyte studies. All cells were derived from primary mixed glial cultures. RESULTS: Significant intercellular differences were observed between glial subtypes: microglia demonstrate the most rapid/extensive particle uptake, followed by astrocytes, with oligodendrocyte precursor cells and oligodendrocytes showing significantly lower uptake. Ultrastructural analyses suggest that magnetic particles are extensively degraded in microglia, but relatively stable in other cells. CONCLUSION: Intercellular differences in particle uptake and handling exist between the major neuroglial subtypes. This has important implications for the utility of the magnetic particle platform for neurobiological applications including genetic modification, transplant cell labeling and biomolecule delivery to mixed CNS cell populations

A Biological Global Positioning System: Considerations for Tracking Stem Cell Behaviors in the Whole Body

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied stem cell therapy in medical practice remains the lack of efficient stem cell tracking methods. As a result, the fate of the vast majority of stem cells transplanted in the human central nervous system (CNS), particularly in the detrimental effects, remains unknown. The paucity of knowledge concerning basic stem cell biology—survival, migration, differentiation, integration in real-time when transplanted into damaged CNS remains a bottleneck in the attempt to design stem cell therapies for CNS diseases. Even though excellent histological techniques remain as the gold standard, no good in vivo techniques are currently available to assess the transplanted graft for migration, differentiation, or survival. To address these issues, herein we propose strategies to investigate the lineage fate determination of derived human embryonic stem cells (hESC) transplanted in vivo into the CNS. Here, we describe a comprehensive biological Global Positioning System (bGPS) to track transplanted stem cells. But, first, we review, four currently used standard methods for tracking stem cells in vivo: magnetic resonance imaging (MRI), bioluminescence imaging (BLI), positron emission tomography (PET) imaging and fluorescence imaging (FLI) with quantum dots. We summarize these modalities and propose criteria that can be employed to rank the practical usefulness for specific applications. Based on the results of this review, we argue that additional qualities are still needed to advance these modalities toward clinical applications. We then discuss an ideal procedure for labeling and tracking stem cells in vivo, finally, we present a novel imaging system based on our experiments

Determining The Fate Of Bone Marrow Mononuclear Cells In Tissue Engineered Vascular Grafts Using Mri

The most widely used method of creating tissue engineered vascular grafts (TEVGs) for in vivo implantation consists of seeding autologous bone marrow cells (BMCs) onto biodegradable scaffolds. In this model of TEVG development it has traditionally been thought that stem cells and endothelial progenitor cells (EPCs) within the seeded bone marrow population gave rise to the cells of the neovessel. Recent work in our lab indicates that the seeded BMCs are not incorporated into the neovessel and are actually rapidly lost from the implanted scaffold. Here we show the feasibility of noninvasively monitoring this process by tracking ultrasmall superparamagnetic iron oxide (USPIO) labeled macrophages with MRI. Murine macrophages were labeled with USPIO through in vitro culture in media containing 2mg/ml of USPIO. The USPIO-labeled macrophages were seeded onto polyglycolic acid (PGA) scaffolds that were surgically implanted as inferior vena cava interposition grafts in SCID/bg mice. Images were then obtained using a 4.7T Bruker horizontal bore scanner with an optimized RARE spin echo sequence and a multislice-multiecho sequence to determine the T2 relaxation time with serial imaging. The T2 signal was found to be significantly lower immediately following implantation of the USPIO labeled scaffolds (T2 = 44±6.8 vs. 71±10.2), but increased rapidly to a value identical to that of control implants seeded with unlabeled macrophages (T2 = 63±12 vs. 63±14). This strongly indicates the rapid loss of seeded cells from the scaffolds, a finding verified using Prussian blue staining for iron containing macrophages on histological sections of explanted TEVGs. Our findings provide further support for the paradigm shift away from BMC neovessel incorporation towards the host cell based population of implanted TEVGs. Furthermore, we demonstrate one of the first successful applications of noninvasive MR imaging for serial study of cellular level processes in tissue engineering

In vivo MRI of endogenous stem/progenitor cell migration from subventricular zone in normal and injured developing brains

Understanding the alterations of migratory activities of the endogenous neural stem/progenitor cells (NSPs) in injured developing brains is becoming increasingly imperative for curative reasons. In this study, 10-day-old neonatal rats with and without hypoxic-ischemic (HI) insult at postnatal day 7 were injected intraventricularly with micron-sized iron oxide particles (MPIOs), followed by serial high-resolution MRI at 7 T for 2 weeks. MRI findings were correlated to the histological analysis using iron staining and several immunohistochemical double staining. The results indicated that in normal and HI-injured brains the NSPs from the subventricular zone (SVZ) were labeled by MPIOs, and migrated as newly created cells (iron+/BrdU+), neuroblasts (iron+/nestin+), astrocytes or astrocytes-like progenitor cells (iron+/GFAP+), and mature neurons (iron+/NeuN+). In normal brains, the endogenous NSPs mainly exhibited a tangential pattern in both rostral and caudal directions. The NSP radial migratory pattern could be observed in some rats. In the HI-injured brains during the same developmental period, the NSPs mainly migrated towards the HI lesion sites. The tangential, rostrocaudal migrations could be observed but impaired. These findings suggest that the NSP migratory pathways in SVZ change in response to the HI insult, likely due to the self-repairing efforts known in the neonatal brains. The MRI approach demonstrated here is potentially applicable to the in vivo and longitudinal study of NSP cell activities in developing brains under normal and pathological conditions and in therapeutic interventions. © 2009 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging

The study of neurogenesis and neural progenitor cells (NPCs) is important across the biomedical spectrum, from learning about normal brain development and studying disease to engineering new strategies in regenerative medicine. In adult mammals, NPCs proliferate in two main areas of the brain, the subventricular zone (SVZ) and the subgranular zone, and continue to migrate even after neurogenesis has ceased within the rest of the brain. In healthy animals, NPCs migrate along the rostral migratory stream (RMS) from the SVZ to the olfactory bulb, and in diseased animals, NPCs migrate toward lesions such as stroke and tumors. Here we review how MRI-based cell tracking using iron oxide particles can be used to monitor and quantify NPC migration in the intact rodent brain, in a serial and relatively non-invasive fashion. NPCs can either be labeled directly in situ by injecting particles into the lateral ventricle or RMS, where NPCs can take up particles, or cells can be harvested and labeled in vitro, then injected into the brain. For in situ labeling experiments, the particle type, injection site, and image analysis methods have been optimized and cell migration toward stroke and multiple sclerosis lesions has been investigated. Delivery of labeled exogenous NPCs has allowed imaging of cell migration toward more sites of neuropathology, which may enable new diagnostic and therapeutic opportunities for as-of-yet untreatable neurological diseases