Guzman, R., et al.: Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc. Natl. Acad. Sci. 104, 10211-10216

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2007; 104(24):10211-6. DOI: 10.1073/pnas.0608519104
Source: PubMed


Noninvasive monitoring of stem cells, using high-resolution molecular imaging, will be instrumental to improve clinical neural transplantation strategies. We show that labeling of human central nervous system stem cells grown as neurospheres with magnetic nanoparticles does not adversely affect survival, migration, and differentiation or alter neuronal electrophysiological characteristics. Using MRI, we show that human central nervous system stem cells transplanted either to the neonatal, the adult, or the injured rodent brain respond to cues characteristic for the ambient microenvironment resulting in distinct migration patterns. Nanoparticle-labeled human central nervous system stem cells survive long-term and differentiate in a site-specific manner identical to that seen for transplants of unlabeled cells. We also demonstrate the impact of graft location on cell migration and describe magnetic resonance characteristics of graft cell death and subsequent clearance. Knowledge of migration patterns and implementation of noninvasive stem cell tracking might help to improve the design of future clinical neural stem cell transplantation.

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Available from: Raphael Guzman, Jan 08, 2014
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    • "In addition to the recruitment of endogenous NSCs and NPCs, recently popularized cell-based therapies for various CNS diseases and injuries rely primarily on the application of exogenous NPCs. Neuronal and glial progenitors have been successfully used in transplantation studies as a source of cells to replace damaged or lost brain cells because they give rise to neuronal and glial cell lineages [6]. Preliminary work has shown the propensity of NSCs to migrate toward areas affected by brain pathology; for example, they may be useful in anticancer treatment to deliver therapeutic proteins and genes to remove malignant brain tumors or may provide therapeutic improvement for neural repair through the delivery of growth factors, cytokines or neurotrophins [7], [8]. "
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    ABSTRACT: The purpose of this study was to generate quadruple fluorescent protein (QFP) transgenic mice as a source for QFP-expressing neural stem and progenitor cells (NSCs/NPCs) that could be utilized as a tool for transplantation research. When undifferentiated, these NSCs only express cyan fluorescent protein (CFP); however, upon neuronal differentiation, the cells express yellow fluorescent protein (YFP). During astrocytic differentiation, the cells express green fluorescent protein (GFP), and during oligodendrocytic differentiation, the cells express red fluorescent protein (DsRed). Using immunocytochemistry, immunoblotting, flow cytometry and electrophysiology, quadruple transgenic NPCs (Q-NPCs) and GFP-sorted NPCs were comprehensively characterized in vitro. Overall, the various transgenes did not significantly affect proliferation and differentiation of transgenic NPCs in comparison to wild-type NPCs. In contrast to a strong CFP and GFP expression in vitro, NPCs did not express YFP and dsRed either during proliferation or after differentiation in vitro. GFP-positive sorted NPCs, expressing GFP under the control of the human GFAP promoter, demonstrated a significant improvement in astroglial differentiation in comparison to GFP-negative sorted NPCs. In contrast to non-sorted and GFP-positive sorted NPCs, GFP-negative sorted NPCs demonstrated a high proportion of neuronal differentiation and proved to be functional in vitro. At 6 weeks after the intracerebroventricular transplantation of Q-NPCs into neonatal wild-type mice, CFP/DCX (doublecortin) double-positive transplanted cells were observed. The Q-NPCs did not express any other fluorescent proteins and did not mature into neuronal or glial cells. Although this model failed to visualize NPC differentiation in vivo, we determined that activation of the NPC glial fibrillary acid protein (GFAP) promoter, as indicated by GFP expression, can be used to separate neuronal and glial progenitors as a valuable tool for transplantation studies.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Various studies have revealed that tracking transplanted (stem) cells in SCI and stroke is perfectly feasible. Such modalities can be linked to stem cell transplantation methods for facilitating translation of stem cell transplantation from the basic research into the clinic.[5888] As it has been described previously, MRI cell imaging has several advantages over other techniques such as PET, SPECT, CT, and ultrasound that make it more compatible to clinical grade cell monitoring purpose. "
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    ABSTRACT: Nowadays, scientific findings in the field of regeneration of nervous system have revealed the possibility of stem cell based therapies for damaged brain tissue related disorders like stroke. Furthermore, to achieve desirable outcomes from cellular therapies, one needs to monitor the migration, engraftment, viability, and also functional fate of transplanted stem cells. Magnetic resonance imaging is an extremely versatile technique for this purpose, which has been broadly used to study stroke and assessment of therapeutic role of stem cells. In this review we searched in PubMed search engine by using following keywords; "Stem Cells", "Cell Tracking", "Stroke", "Stem Cell Transplantation", "Nanoparticles", and "Magnetic Resonance Imaging" as entry terms and based on the mentioned key words, the search period was set from 1976 to 2012. The main purpose of this article is describing various advantages of molecular and magnetic resonance imaging of stem cells, with focus on translation of stem cell research to clinical research.
    Full-text · Article · May 2014 · Journal of research in medical sciences
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    • "Labeling stem or progenitor cells with SPIONs allow their migration pattern to be non-invasively monitored in vivo with MRI. This has the possibility to help monitor stem cell therapy in the treatment of diseases such as myocardial infarctions,23 neurological diseases, and cancer.24 Success has recently been reported in a rat model of Huntington’s disease.24 Figure 3 shows an MRI of SPION-labeled mesenchymal stem cells (MSCs) in vivo, which could be imaged 60 days post-implantation. "
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    ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPIONs) are an exciting advancement in the field of nanotechnology. They expand the possibilities of noninvasive analysis and have many useful properties, making them potential candidates for numerous novel applications. Notably, they have been shown that they can be tracked by magnetic resonance imaging (MRI) and are capable of conjugation with various cell types, including stem cells. In-depth research has been undertaken to establish these benefits, so that a deeper level of understanding of stem cell migratory pathways and differentiation, tumor migration, and improved drug delivery can be achieved. Stem cells have the ability to treat and cure many debilitating diseases with limited side effects, but a main problem that arises is in the noninvasive tracking and analysis of these stem cells. Recently, researchers have acknowledged the use of SPIONs for this purpose and have set out to establish suitable protocols for coating and attachment, so as to bring MRI tracking of SPION-labeled stem cells into common practice. This review paper explains the manner in which SPIONs are produced, conjugated, and tracked using MRI, as well as a discussion on their limitations. A concise summary of recently researched magnetic particle coatings is provided, and the effects of SPIONs on stem cells are evaluated, while animal and human studies investigating the role of SPIONs in stem cell tracking will be explored.
    Full-text · Article · Mar 2014 · International Journal of Nanomedicine
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