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1
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Borda M, Aquino JB, Mazzone GL. Cell-based experimental strategies for myelin repair in multiple sclerosis. J Neurosci Res 2023; 101:86-111. [PMID: 36164729 DOI: 10.1002/jnr.25129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/21/2022] [Accepted: 09/09/2022] [Indexed: 11/10/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), diagnosed at a mean age of 32 years. CNS glia are crucial players in the onset of MS, primarily involving astrocytes and microglia that can cause/allow massive oligodendroglial cells death, without immune cell infiltration. Current therapeutic approaches are aimed at modulating inflammatory reactions during relapsing episodes, but lack the ability to induce very significant repair mechanisms. In this review article, different experimental approaches based mainly on the application of different cell types as therapeutic strategies applied for the induction of myelin repair and/or the amelioration of the disease are discussed. Regarding this issue, different cell sources were applied in various experimental models of MS, with different results, both in significant improvements in remyelination and the reduction of neuroinflammation and glial activation, or in neuroprotection. All cell types tested have advantages and disadvantages, which makes it difficult to choose a better option for therapeutic application in MS. New strategies combining cell-based treatment with other applications would result in further improvements and would be good candidates for MS cell therapy and myelin repair.
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Affiliation(s)
- Maximiliano Borda
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina
| | - Jorge B Aquino
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
| | - Graciela L Mazzone
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Derqui, Pilar, Buenos Aires, Argentina.,CONICET, Comisión Nacional de Investigaciones Científicas y Técnicas
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2
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Khodanovich MY, Anan’ina TV, Krutenkova EP, Akulov AE, Kudabaeva MS, Svetlik MV, Tumentceva YA, Shadrina MM, Naumova AV. Challenges and Practical Solutions to MRI and Histology Matching and Measurements Using Available ImageJ Software Tools. Biomedicines 2022; 10:1556. [PMID: 35884861 PMCID: PMC9313422 DOI: 10.3390/biomedicines10071556] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 11/29/2022] Open
Abstract
Traditionally histology is the gold standard for the validation of imaging experiments. Matching imaging slices and histological sections and the precise outlining of corresponding tissue structures are difficult. Challenges are based on differences in imaging and histological slice thickness as well as tissue shrinkage and alterations after processing. Here we describe step-by-step instructions that might be used as a universal pathway to overlay MRI and histological images and for a correlation of measurements between imaging modalities. The free available (Fiji is just) ImageJ software tools were used for regions of interest transformation (ROIT) and alignment using a rat brain MRI as an example. The developed ROIT procedure was compared to a manual delineation of rat brain structures. The ROIT plugin was developed for ImageJ to enable an automatization of the image processing and structural analysis of the rodent brain.
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Affiliation(s)
- Marina Y. Khodanovich
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Tatyana V. Anan’ina
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Elena P. Krutenkova
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Andrey E. Akulov
- Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 10 Lavrentyeva Avenue, 630090 Novosibirsk, Russia;
| | - Marina S. Kudabaeva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Mikhail V. Svetlik
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Yana A. Tumentceva
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Maria M. Shadrina
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
| | - Anna V. Naumova
- Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, Russia. 36, Lenina Ave., 634050 Tomsk, Russia; (T.V.A.); len-- (E.P.K.); (M.S.K.); (M.V.S.); (Y.A.T.); (M.M.S.); (A.V.N.)
- Department of Radiology, University of Washington, 850 Republican Street, Seattle, WA 98109, USA
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Kim IK, Park JH, Kim B, Hwang KC, Song BW. Recent advances in stem cell therapy for neurodegenerative disease: Three dimensional tracing and its emerging use. World J Stem Cells 2021; 13:1215-1230. [PMID: 34630859 PMCID: PMC8474717 DOI: 10.4252/wjsc.v13.i9.1215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative disease is a brain disorder caused by the loss of structure and function of neurons that lowers the quality of human life. Apart from the limited potential for endogenous regeneration, stem cell-based therapies hold considerable promise for maintaining homeostatic tissue regeneration and enhancing plasticity. Despite many studies, there remains insufficient evidence for stem cell tracing and its correlation with endogenous neural cells in brain tissue with three-dimensional structures. Recent advancements in tissue optical clearing techniques have been developed to overcome the existing shortcomings of cross-sectional tissue analysis in thick and complex tissues. This review focuses on recent progress of stem cell treatments to improve neurodegenerative disease, and introduces tissue optical clearing techniques that can implement a three-dimensional image as a proof of concept. This review provides a more comprehensive understanding of stem cell tracing that will play an important role in evaluating therapeutic efficacy and cellular interrelationship for regeneration in neurodegenerative diseases.
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Affiliation(s)
- Il-Kwon Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Jun-Hee Park
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Bomi Kim
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City 22711, South Korea
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangwon-do 25601, South Korea.
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Cayre M, Falque M, Mercier O, Magalon K, Durbec P. Myelin Repair: From Animal Models to Humans. Front Cell Neurosci 2021; 15:604865. [PMID: 33935649 PMCID: PMC8079744 DOI: 10.3389/fncel.2021.604865] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/15/2021] [Indexed: 12/20/2022] Open
Abstract
It is widely thought that brain repair does not occur, but myelin regeneration provides clear evidence to the contrary. Spontaneous remyelination may occur after injury or in multiple sclerosis (MS). However, the efficiency of remyelination varies considerably between MS patients and between the lesions of each patient. Myelin repair is essential for optimal functional recovery, so a profound understanding of the cells and mechanisms involved in this process is required for the development of new therapeutic strategies. In this review, we describe how animal models and modern cell tracing and imaging methods have helped to identify the cell types involved in myelin regeneration. In addition to the oligodendrocyte progenitor cells identified in the 1990s as the principal source of remyelinating cells in the central nervous system (CNS), other cell populations, including subventricular zone-derived neural progenitors, Schwann cells, and even spared mature oligodendrocytes, have more recently emerged as potential contributors to CNS remyelination. We will also highlight the conditions known to limit endogenous repair, such as aging, chronic inflammation, and the production of extracellular matrix proteins, and the role of astrocytes and microglia in these processes. Finally, we will present the discrepancies between observations in humans and in rodents, discussing the relationship of findings in experimental models to myelin repair in humans. These considerations are particularly important from a therapeutic standpoint.
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Affiliation(s)
- Myriam Cayre
- Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM-UMR 7288), Marseille, France
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5
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Tissue-Specific Ferritin- and GFP-Based Genetic Vectors Visualize Neurons by MRI in the Intact and Post-Ischemic Rat Brain. Int J Mol Sci 2020; 21:ijms21238951. [PMID: 33255702 PMCID: PMC7728074 DOI: 10.3390/ijms21238951] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
(1) Background: Neurogenesis is considered to be a potential brain repair mechanism and is enhanced in stroke. It is difficult to reconstruct the neurogenesis process only from the histological sections taken from different animals at different stages of brain damage and restoration. Study of neurogenesis would greatly benefit from development of tissue-specific visualization probes. (2) Purpose: The study aimed to explore if overexpression of ferritin, a nontoxic iron-binding protein, under a doublecortin promoter can be used for non-invasive visualization of neurogenesis using magnetic resonance imaging (MRI). (3) Methods: Ferritin heavy chain (FerrH) was expressed in the adeno-associated viral backbone (AAV) under the doublecortin promoter (pDCX), specific for young neurons, in the viral construct AAV-pDCX-FerrH. Expression of the enhanced green fluorescent protein (eGFP) was used as an expression control (AAV-pDCX-eGFP). The viral vectors or phosphate-buffered saline (PBS) were injected intracerebrally into 18 adult male Sprague–Dawley rats. Three days before injection, rats underwent transient middle-cerebral-artery occlusion or sham operation. Animals were subjected to In vivo MRI study before surgery and on days 7, 14, 21, and 28 days after injection using a Bruker BioSpec 11.7 T scanner. Brain sections obtained on day 28 after injection were immunostained for ferritin, young (DCX) and mature (NeuN) neurons, and activated microglia/macrophages (CD68). Additionally, RT-PCR was performed to confirm ferritin expression. (4) Results: T2* images in post-ischemic brains of animals injected with AAV-pDCX-FerrH showed two distinct zones of MRI signal hypointensity in the ipsilesioned hemisphere starting from 14 days after viral injection—in the ischemic lesion and near the lateral ventricle and subventricular zone (SVZ). In sham-operated animals, only one zone of hypointensity near the lateral ventricle and SVZ was revealed. Immunochemistry showed that ferritin-expressing cells in ischemic lesions were macrophages (88.1%), while ferritin-expressing cells near the lateral ventricle in animals both after ischemia and sham operation were mostly mature (55.7% and 61.8%, respectively) and young (30.6% and 7.1%, respectively) neurons. RT-PCR confirmed upregulated expression of ferritin in the caudoputamen and corpus callosum. Surprisingly, in animals injected with AAV-pDCX-eGFP we similarly observed two zones of hypointensity on T2* images. Cellular studies also showed the presence of mature (81.5%) and young neurons (6.1%) near the lateral ventricle in both postischemic and sham-operated animals, while macrophages in ischemic lesions were ferritin-positive (98.2%). (5) Conclusion: Ferritin overexpression induced by injection of AAV-pDCX-FerrH was detected by MRI using T2*-weighted images, which was confirmed by immunochemistry showing ferritin in young and mature neurons. Expression of eGFP also caused a comparable reduced MR signal intensity in T2*-weighted images. Additional studies are needed to investigate the potential and tissue-specific features of the use of eGFP and ferritin expression in MRI studies.
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DCX + neuronal progenitors contribute to new oligodendrocytes during remyelination in the hippocampus. Sci Rep 2020; 10:20095. [PMID: 33208869 PMCID: PMC7674453 DOI: 10.1038/s41598-020-77115-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
A pool of different types of neural progenitor cells resides in the adult hippocampus. Apart from doublecortin-expressing (DCX+) neuronal progenitor cells (NPCs), the hippocampal parenchyma also contains oligodendrocyte precursor cells (OPCs), which can differentiate into myelinating oligodendrocytes. It is not clear yet to what extent the functions of these different progenitor cell types overlap and how plastic these cells are in response to pathological processes. The aim of this study was to investigate whether hippocampal DCX+ NPCs can generate new oligodendrocytes under conditions in which myelin repair is required. For this, the cell fate of DCX-expressing NPCs was analyzed during cuprizone-induced demyelination and subsequent remyelination in two regions of the hippocampal dentate gyrus of DCX-CreERT2/Flox-EGFP transgenic mice. In this DCX reporter model, the number of GFP+ NPCs co-expressing Olig2 and CC1, a combination of markers typically found in mature oligodendrocytes, was significantly increased in the hippocampal DG during remyelination. In contrast, the numbers of GFP+PDGFRα+ cells, as well as their proliferation, were unaffected by de- or remyelination. During remyelination, a higher portion of newly generated BrdU-labeled cells were GFP+ NPCs and there was an increase in new oligodendrocytes derived from these proliferating cells (GFP+Olig2+BrdU+). These results suggest that DCX-expressing NPCs were able to contribute to the generation of mature oligodendrocytes during remyelination in the adult hippocampus.
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Barati S, Ragerdi Kashani I, Moradi F, Tahmasebi F, Mehrabi S, Barati M, Joghataei MT. Mesenchymal stem cell mediated effects on microglial phenotype in cuprizone-induced demyelination model. J Cell Biochem 2019; 120:13952-13964. [PMID: 30963634 DOI: 10.1002/jcb.28670] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/06/2019] [Accepted: 02/28/2019] [Indexed: 12/23/2022]
Abstract
Microglial cells have an essential role in neurodegenerative disorders, such as multiple sclerosis. They are divided into two subgroups: M1 and M2 phenotypes. Mesenchymal stem cells (MSC), with neuroprotective and immunomodulating properties, could improve these diseases. We evaluate the immunomodulating effects of MSC on microglial phenotypes and the improvement of demyelination in a cuprizone (CPZ) model of multiple sclerosis (MS). For inducing the chronic demyelination model, C57BL6 mice were given a diet with 0.2% CPZ (w/w) for 12 weeks. In the MSC group, cells were transplanted into the right lateral ventricle of mice. The expression of targeted genes was assessed by real-time polymerase chain reaction. M1 and M2 microglial phenotypes were assessed by immunohistochemistry of inducible nitric oxide synthase (iNOS) and Arg-1, respectively. Remyelination was studied by luxal fast blue (LFB) staining and electron microscopy (EM). We found that MSC transplantation reduced the expression level of M1-specific messenger RNA (mRNA; iNOS and CD86) but increased the expression level of M2 specific genes (CD206, Arg-1, and CX3CR1) in comparison to the CPZ group. Moreover, cell therapy significantly decreased the M1 marker (iNOS+ cells), but M2 marker (Arg-1+ cells) significantly increased in comparison with the CPZ group. In addition, MSC treatment significantly increased the CX3CL1 expression level in comparison with the CPZ group and led to improvement in remyelination, which was confirmed by LFB and EM images. The results showed that MSC transplantation increases the M2 and decreases the M1 phenotype in MS. This change was accompanied by decrease in demyelination and axonal injury and indicated that MSCs have a positive effect on MS by modification of microglia cells.
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Affiliation(s)
- Shirin Barati
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fateme Moradi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tahmasebi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soraya Mehrabi
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Barati
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
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Naeyaert M, Roose D, Mai Z, Keliris A, Sijbers J, Van der Linden A, Verhoye M. Normalized averaged range (nAR), a robust quantification method for MPIO-content. JOURNAL OF MAGNETIC RESONANCE (SAN DIEGO, CALIF. : 1997) 2019; 300:18-27. [PMID: 30684825 DOI: 10.1016/j.jmr.2018.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/06/2018] [Accepted: 12/20/2018] [Indexed: 06/09/2023]
Abstract
Micron-sized paramagnetic iron oxide particles (MPIO) are commonly used as contrast agents in magnetic resonance imaging (MRI) that produce negative contrast enhancement, i.e. darkening, on T2*-weighted images. However, estimation and quantification of MPIO in vivo is still challenging. This limitation mainly arises from smearing and displacement of the negative contrast of the MPIO, so-called blooming, potentially leading to false-positive detection. Further, the bias field induced by the MR coils also hinders visualization and quantification of the MPIO. To mitigate these drawbacks, a positive contrast image can be generated, for example by using a frequency offset technique, which can significantly improve the accuracy of quantification methods. In this research, we introduce the normalized average range (nAR) as a new way to quantify the relative MPIO content within a study. The method compares the average value of test ROIs to that of a control ROI in range filtered images. The nAR can be used on both positive and negative contrast images. The nAR was tested on agar phantoms containing various MPIO concentrations, and on a rostral migration model for MPIO labeled stem cells in mice. The amount of MPIO was quantified for biased and unbiased data, and both for positive and negative contrast images. In addition, the presence of MPIOs in the olfactory bulb was verified by histology. The results show the nAR can indicate the presence and relative content of MPIO for both negative and positive images. However, the nAR showed slightly higher sensitivity in optimized positive contrast images compared to negative contrast images. In all cases, the bias field played a minor role in the quantification, making debiasing less of a concern. The dependency of the nAR values on the MPIO content in the ROI was further validated histologically. Thus, the nAR provides a robust and reliable tool for quantification of MPIO in mice.
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Affiliation(s)
- Maarten Naeyaert
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
| | - Dimitri Roose
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
| | - Zhenhua Mai
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
| | - Aneta Keliris
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
| | - Jan Sijbers
- imec-Vision Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
| | - Annemie Van der Linden
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
| | - Marleen Verhoye
- Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium
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Mallett CL, Shuboni-Mulligan DD, Shapiro EM. Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging. Front Neurosci 2019; 12:995. [PMID: 30686969 PMCID: PMC6337062 DOI: 10.3389/fnins.2018.00995] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 12/11/2018] [Indexed: 12/19/2022] Open
Abstract
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.
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Affiliation(s)
- Christiane L. Mallett
- Molecular and Cellular Imaging Laboratory, Department of Radiology, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Dorela D. Shuboni-Mulligan
- Molecular and Cellular Imaging Laboratory, Department of Radiology, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Erik M. Shapiro
- Molecular and Cellular Imaging Laboratory, Department of Radiology, Michigan State University, East Lansing, MI, United States
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
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10
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Bose RJC, Mattrey RF. Accomplishments and challenges in stem cell imaging in vivo. Drug Discov Today 2018; 24:492-504. [PMID: 30342245 DOI: 10.1016/j.drudis.2018.10.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 09/24/2018] [Accepted: 10/13/2018] [Indexed: 02/08/2023]
Abstract
Stem cell therapies have demonstrated promising preclinical results, but very few applications have reached the clinic owing to safety and efficacy concerns. Translation would benefit greatly if stem cell survival, distribution and function could be assessed in vivo post-transplantation, particularly in patients. Advances in molecular imaging have led to extraordinary progress, with several strategies being deployed to understand the fate of stem cells in vivo using magnetic resonance, scintigraphy, PET, ultrasound and optical imaging. Here, we review the recent advances, challenges and future perspectives and opportunities in stem cell tracking and functional assessment, as well as the advantages and challenges of each imaging approach.
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Affiliation(s)
- Rajendran J C Bose
- Department of Radiology and Advanced Imaging Research Center, 5323 Harry Hines Blvd, UT Southwestern Medical Center, Dallas, TX 75390-8514, USA; Current affiliation: Molecular Imaging Program at Stanford (MIPS) and the Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Stanford, CA 94305-5427, USA
| | - Robert F Mattrey
- Department of Radiology and Advanced Imaging Research Center, 5323 Harry Hines Blvd, UT Southwestern Medical Center, Dallas, TX 75390-8514, USA.
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11
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Serwanski DR, Rasmussen AL, Brunquell CB, Perkins SS, Nishiyama A. Sequential Contribution of Parenchymal and Neural Stem Cell-Derived Oligodendrocyte Precursor Cells toward Remyelination. NEUROGLIA (BASEL, SWITZERLAND) 2018; 1:91-105. [PMID: 30662979 PMCID: PMC6335037 DOI: 10.3390/neuroglia1010008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In the adult mammalian forebrain, oligodendrocyte precursor cells (OPCs), also known as NG2 glia are distributed ubiquitously throughout the gray and white matter. They remain proliferative and continuously generate myelinating oligodendrocytes throughout life. In response to a demyelinating insult, OPCs proliferate rapidly and differentiate into oligodendrocytes which contribute to myelin repair. In addition to OPCs, neural stem cells (NSCs) in the subventricular zone (SVZ) also contribute to remyelinating oligodendrocytes, particularly in demyelinated lesions in the vicinity of the SVZ, such as the corpus callosum. To determine the relative contribution of local OPCs and NSC-derived cells toward myelin repair, we performed genetic fate mapping of OPCs and NSCs and compared their ability to generate oligodendrocytes after acute demyelination in the corpus callosum created by local injection of α-lysophosphatidylcholine (LPC). We have found that local OPCs responded rapidly to acute demyelination, expanded in the lesion within seven days, and produced oligodendrocytes by two weeks after lesioning. By contrast, NSC-derived NG2 cells did not significantly increase in the lesion until four weeks after demyelination and generated fewer oligodendrocytes than parenchymal OPCs. These observations suggest that local OPCs could function as the primary responders to repair acutely demyelinated lesion, and that NSCs in the SVZ contribute to repopulating OPCs following their depletion due to oligodendrocyte differentiation.
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Affiliation(s)
- David R Serwanski
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Andrew L Rasmussen
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Christopher B Brunquell
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Scott S Perkins
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
- Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA
- Institute for Brain and Cognitive Science, University of Connecticut, Storrs, CT 06269, USA
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12
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Abstract
Neuron-glia antigen 2-expressing glial cells (NG2 glia) serve as oligodendrocyte progenitors during development and adulthood. However, recent studies have shown that these cells represent not only a transitional stage along the oligodendroglial lineage, but also constitute a specific cell type endowed with typical properties and functions. Namely, NG2 glia (or subsets of NG2 glia) establish physical and functional interactions with neurons and other central nervous system (CNS) cell types, that allow them to constantly monitor the surrounding neuropil. In addition to operating as sensors, NG2 glia have features that are expected for active modulators of neuronal activity, including the expression and release of a battery of neuromodulatory and neuroprotective factors. Consistently, cell ablation strategies targeting NG2 glia demonstrate that, beyond their role in myelination, these cells contribute to CNS homeostasis and development. In this review, we summarize and discuss the advancements achieved over recent years toward the understanding of such functions, and propose novel approaches for further investigations aimed at elucidating the multifaceted roles of NG2 glia.
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13
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Bjelobaba I, Begovic-Kupresanin V, Pekovic S, Lavrnja I. Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis. J Neurosci Res 2018; 96:1021-1042. [PMID: 29446144 DOI: 10.1002/jnr.24224] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 01/15/2018] [Accepted: 01/25/2018] [Indexed: 12/15/2022]
Abstract
Multiple sclerosis (MS) is a chronic, progressive disorder of the central nervous system (CNS) that affects more than two million people worldwide. Several animal models resemble MS pathology; the most employed are experimental autoimmune encephalomyelitis (EAE) and toxin- and/or virus-induced demyelination. In this review we will summarize our knowledge on the utility of different animal models in MS research. Although animal models cannot replicate the complexity and heterogeneity of the MS pathology, they have proved to be useful for the development of several drugs approved for treatment of MS patients. This review focuses on EAE because it represents both clinical and pathological features of MS. During the past decades, EAE has been effective in illuminating various pathological processes that occur during MS, including inflammation, CNS penetration, demyelination, axonopathy, and neuron loss mediated by immune cells.
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Affiliation(s)
- Ivana Bjelobaba
- Institute for Biological Research "Sinisa Stankovic," Department of Neurobiology, University of Belgrade, Belgrade, Serbia
| | | | - Sanja Pekovic
- Institute for Biological Research "Sinisa Stankovic," Department of Neurobiology, University of Belgrade, Belgrade, Serbia
| | - Irena Lavrnja
- Institute for Biological Research "Sinisa Stankovic," Department of Neurobiology, University of Belgrade, Belgrade, Serbia
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14
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Baxi EG, DeBruin J, Jin J, Strasburger HJ, Smith MD, Orthmann-Murphy JL, Schott JT, Fairchild AN, Bergles DE, Calabresi PA. Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone-induced demyelination. Glia 2017; 65:2087-2098. [PMID: 28940645 DOI: 10.1002/glia.23229] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 08/20/2017] [Accepted: 08/23/2017] [Indexed: 11/10/2022]
Abstract
The regeneration of oligodendrocytes is a crucial step in recovery from demyelination, as surviving oligodendrocytes exhibit limited structural plasticity and rarely form additional myelin sheaths. New oligodendrocytes arise through the differentiation of platelet-derived growth factor receptor α (PDGFRα) expressing oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. Although there has been detailed investigation of the behavior of these progenitors in white matter, recent studies suggest that disease burden in multiple sclerosis (MS) is more strongly correlated with gray matter atrophy. The timing and efficiency of remyelination in gray matter is distinct from white matter, but the dynamics of OPCs that contribute to these differences have not been defined. Here, we used in vivo genetic fate tracing to determine the behavior of OPCs in gray and white matter regions in response to cuprizone-induced demyelination. Our studies indicate that the temporal dynamics of OPC differentiation varies significantly between white and gray matter. While OPCs rapidly repopulate the corpus callosum and mature into CC1 expressing mature oligodendrocytes, OPC differentiation in the cingulate cortex and hippocampus occurs much more slowly, resulting in a delay in remyelination relative to the corpus callosum. The protracted maturation of OPCs in gray matter may contribute to greater axonal pathology and disease burden in MS.
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Affiliation(s)
- Emily G Baxi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph DeBruin
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jing Jin
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hayley J Strasburger
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Matthew D Smith
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jennifer L Orthmann-Murphy
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical School, Baltimore, Maryland
| | - Jason T Schott
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Amanda N Fairchild
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dwight E Bergles
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical School, Baltimore, Maryland
| | - Peter A Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical School, Baltimore, Maryland
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15
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Hyperpolarized 13C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model. Proc Natl Acad Sci U S A 2017; 114:E6982-E6991. [PMID: 28760957 DOI: 10.1073/pnas.1613345114] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Proinflammatory mononuclear phagocytes (MPs) play a crucial role in the progression of multiple sclerosis (MS) and other neurodegenerative diseases. Despite advances in neuroimaging, there are currently limited available methods enabling noninvasive detection of MPs in vivo. Interestingly, upon activation and subsequent differentiation toward a proinflammatory phenotype MPs undergo metabolic reprogramming that results in increased glycolysis and production of lactate. Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) is a clinically translatable imaging method that allows noninvasive monitoring of metabolic pathways in real time. This method has proven highly useful to monitor the Warburg effect in cancer, through MR detection of increased HP [1-13C]pyruvate-to-lactate conversion. However, to date, this method has never been applied to the study of neuroinflammation. Here, we questioned the potential of 13C MRSI of HP [1-13C]pyruvate to monitor the presence of neuroinflammatory lesions in vivo in the cuprizone mouse model of MS. First, we demonstrated that 13C MRSI could detect a significant increase in HP [1-13C]pyruvate-to-lactate conversion, which was associated with a high density of proinflammatory MPs. We further demonstrated that the increase in HP [1-13C]lactate was likely mediated by pyruvate dehydrogenase kinase 1 up-regulation in activated MPs, resulting in regional pyruvate dehydrogenase inhibition. Altogether, our results demonstrate a potential for 13C MRSI of HP [1-13C]pyruvate as a neuroimaging method for assessment of inflammatory lesions. This approach could prove useful not only in MS but also in other neurological diseases presenting inflammatory components.
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16
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Kazanis I, Evans KA, Andreopoulou E, Dimitriou C, Koutsakis C, Karadottir RT, Franklin RJM. Subependymal Zone-Derived Oligodendroblasts Respond to Focal Demyelination but Fail to Generate Myelin in Young and Aged Mice. Stem Cell Reports 2017; 8:685-700. [PMID: 28196689 PMCID: PMC5355571 DOI: 10.1016/j.stemcr.2017.01.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 01/10/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2023] Open
Abstract
Two populations of oligodendrogenic progenitors co-exist within the corpus callosum (CC) of the adult mouse. Local, parenchymal oligodendrocyte progenitor cells (pOPCs) and progenitors generated in the subependymal zone (SEZ) cytogenic niche. pOPCs are committed perinatally and retain their numbers through self-renewing divisions, while SEZ-derived cells are relatively “young,” being constantly born from neural stem cells. We compared the behavior of these populations, labeling SEZ-derived cells using hGFAP:CreErt2 mice, within the homeostatic and regenerating CC of the young-adult and aging brain. We found that SEZ-derived oligodendroglial progenitors have limited self-renewing potential and are therefore not bona fide OPCs but rather “oligodendroblasts” more similar to the neuroblasts of the neurogenic output of the SEZ. In the aged CC their mitotic activity is much reduced, although they still act as a “fast-response element” to focal demyelination. In contrast to pOPCs, they fail to generate mature myelinating oligodendrocytes at all ages studied.
SEZ-derived cells in the CC are oligodendroblasts and not OPCs Oligodendroblasts have limited self-renewal capacity and do not make myelin Oligodendroblasts respond rapidly after demyelination Aging does not affect the oligodendroblast-pOPC balance
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Affiliation(s)
- Ilias Kazanis
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK; Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece.
| | - Kimberley A Evans
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK
| | - Evangelia Andreopoulou
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | - Christina Dimitriou
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | - Christos Koutsakis
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | | | - Robin J M Franklin
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK.
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17
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Hollingsworth E, Khouri J, Imitola J. Endogenous repair and development inspired therapy of neurodegeneration in progressive multiple sclerosis. Expert Rev Neurother 2017; 17:611-629. [DOI: 10.1080/14737175.2017.1287564] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Ethan Hollingsworth
- Laboratory for Neural Stem Cells and Functional Neurogenetics, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
- Division of Neuroimmunology and Multiple Sclerosis and Departments of Neurology and Neuroscience. The Ohio State, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
| | - Jamil Khouri
- Laboratory for Neural Stem Cells and Functional Neurogenetics, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
- Division of Neuroimmunology and Multiple Sclerosis and Departments of Neurology and Neuroscience. The Ohio State, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
| | - Jaime Imitola
- Laboratory for Neural Stem Cells and Functional Neurogenetics, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
- Division of Neuroimmunology and Multiple Sclerosis and Departments of Neurology and Neuroscience. The Ohio State, University Wexner Medical Center, Biomedical Research Tower, Columbus, OH, USA
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18
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Le Blon D, Guglielmetti C, Hoornaert C, Quarta A, Daans J, Dooley D, Lemmens E, Praet J, De Vocht N, Reekmans K, Santermans E, Hens N, Goossens H, Verhoye M, Van der Linden A, Berneman Z, Hendrix S, Ponsaerts P. Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model. J Neuroinflammation 2016; 13:288. [PMID: 27829467 PMCID: PMC5103449 DOI: 10.1186/s12974-016-0756-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/31/2016] [Indexed: 12/22/2022] Open
Abstract
Background Promoting the neuroprotective and repair-inducing effector functions of microglia and macrophages, by means of M2 polarisation or alternative activation, is expected to become a new therapeutic approach for central nervous system (CNS) disorders in which detrimental pro-inflammatory microglia and/or macrophages display a major contribution to the neuropathology. In this study, we present a novel in vivo approach using intracerebral grafting of mesenchymal stem cells (MSC) genetically engineered to secrete interleukin 13 (IL13-MSC). Methods In the first experimental setup, control MSC and IL13-MSC were grafted in the CNS of eGFP+ bone marrow chimaeric C57BL/6 mice to histologically evaluate IL13-mediated expression of several markers associated with alternative activation, including arginase1 and Ym1, on MSC graft-recognising microglia and MSC graft-infiltrating macrophages. In the second experimental setup, IL13-MSC were grafted on the right side (or on both the right and left sides) of the splenium of the corpus callosum in wild-type C57BL/6 mice and in C57BL/6 CX3CR1eGFP/+CCR2RFP/+ transgenic mice. Next, CNS inflammation and demyelination was induced by means of a cuprizone-supplemented diet. The influence of IL13-MSC grafting on neuropathological alterations was monitored by non-invasive T2-weighted magnetic resonance imaging (MRI) and quantitative histological analyses, as compared to cuprizone-treated mice with control MSC grafts and/or cuprizone-treated mice without MSC injection. Results In the first part of this study, we demonstrate that MSC graft-associated microglia and MSC graft-infiltrating macrophages are forced into alternative activation upon grafting of IL13-MSC, but not upon grafting of control MSC. In the second part of this study, we demonstrate that grafting of IL13-MSC, in addition to the recruitment of M2 polarised macrophages, limits cuprizone-induced microgliosis, oligodendrocyte death and demyelination. Furthermore, we here demonstrate that injection of IL13-MSC at both sides of the splenium leads to a superior protective effect as compared to a single injection at one side of the splenium. Conclusions Controlled and localised production of IL13 by means of intracerebral MSC grafting has the potential to modulate cell graft- and pathology-associated microglial/macrophage responses, and to interfere with oligodendrocyte death and demyelinating events in the cuprizone mouse model.
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Affiliation(s)
- Debbie Le Blon
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Caroline Guglielmetti
- Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Chloé Hoornaert
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Alessandra Quarta
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Jasmijn Daans
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Dearbhaile Dooley
- Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium
| | - Evi Lemmens
- Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium
| | - Jelle Praet
- Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Nathalie De Vocht
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Kristien Reekmans
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Eva Santermans
- Center for Statistics, I-Biostat, Hasselt University, Agoralaan building D, 3590, Diepenbeek, Belgium
| | - Niel Hens
- Center for Statistics, I-Biostat, Hasselt University, Agoralaan building D, 3590, Diepenbeek, Belgium.,Centre for Health Economic Research and Modeling Infectious Diseases (Chermid), University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Herman Goossens
- Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Marleen Verhoye
- Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Annemie Van der Linden
- Bio-Imaging Laboratory, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Zwi Berneman
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Sven Hendrix
- Department of Morphology, Biomedical Research Institute, Hasselt University, Agoralaan building C, 3590, Diepenbeek, Belgium
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium. .,Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium. .,Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Campus Drie Eiken (CDE-S6.51), Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium.
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19
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Guglielmetti C, Le Blon D, Santermans E, Salas-Perdomo A, Daans J, De Vocht N, Shah D, Hoornaert C, Praet J, Peerlings J, Kara F, Bigot C, Mai Z, Goossens H, Hens N, Hendrix S, Verhoye M, Planas AM, Berneman Z, van der Linden A, Ponsaerts P. Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages. Glia 2016; 64:2181-2200. [PMID: 27685637 DOI: 10.1002/glia.23053] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/01/2016] [Accepted: 08/11/2016] [Indexed: 02/06/2023]
Abstract
Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T2 -weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL-13 immune gene therapy in cuprizone-treated eGFP+ bone marrow chimeric mice, we provide evidence that IL-13 directs the polarization of both brain-resident microglia and infiltrating macrophages towards an alternatively activated phenotype, thereby promoting the conversion of a pro-inflammatory environment toward an anti-inflammatory environment, as further evidenced by gene expression analyses. Finally, we show that IL-13 immune gene therapy is also able to limit lesion severity in a pre-existing inflammatory environment. In conclusion, these results highlight the potential of IL-13 to modulate microglia/macrophage responses and to improve disease outcome in a mouse model for MS. GLIA 2016;64:2181-2200.
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Affiliation(s)
- Caroline Guglielmetti
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Debbie Le Blon
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Eva Santermans
- Center for Statistics, I-Biostat, Hasselt University, Hasselt, Belgium
| | - Angelica Salas-Perdomo
- Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jasmijn Daans
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Nathalie De Vocht
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Disha Shah
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Chloé Hoornaert
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Jelle Praet
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Jurgen Peerlings
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Firat Kara
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Christian Bigot
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Zhenhua Mai
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.,Icometrix, Leuven, Belgium
| | - Herman Goossens
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Niel Hens
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.,Center for Statistics, I-Biostat, Hasselt University, Hasselt, Belgium.,Centre for Health Economic Research and Modelling Infectious Diseases (Chermid), University of Antwerp, Antwerp, Belgium
| | - Sven Hendrix
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Marleen Verhoye
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Anna M Planas
- Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Zwi Berneman
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Annemie van der Linden
- Bio-Imaging Laboratory, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. .,Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
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20
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Zhang F, Duan X, Lu L, Zhang X, Zhong X, Mao J, Chen M, Shen J. In Vivo Targeted MR Imaging of Endogenous Neural Stem Cells in Ischemic Stroke. Molecules 2016; 21:1143. [PMID: 27589699 PMCID: PMC6273863 DOI: 10.3390/molecules21091143] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/19/2016] [Accepted: 08/26/2016] [Indexed: 12/22/2022] Open
Abstract
Acute ischemic stroke remains a leading cause of death and disability. Endogenous neurogenesis enhanced via activation of neural stem cells (NSCs) could be a promising method for stroke treatment. In vivo targeted tracking is highly desirable for monitoring the dynamics of endogenous NSCs in stroke. Previously, we have successfully realized in vivo targeted MR imaging of endogenous NSCs in normal adult mice brains by using anti-CD15 antibody-conjugated superparamagnetic iron oxide nanoparticles (anti-CD15-SPIONs) as the molecular probe. Herein, we explore the performance of this molecular probe in targeted in vivo tracking of activated endogenous NSCs in ischemic stroke. Our study showed that intraventricular injection of anti-CD15-SPIONs could label activated endogenous NSCs in situ seven days after ischemic stroke, which were detected as enlarged areas of hypo-intense signals on MR imaging at 7.0 T. The treatment of cytosine arabinosine could inhibit the activation of endogenous NSCs, which was featured by the disappearance of areas of hypo-intense signals on MR imaging. Using anti-CD15-SPIONs as imaging probes, the dynamic process of activation of endogenous NSCs could be readily monitored by in vivo MR imaging. This targeted imaging strategy would be of great benefit to develop a new therapeutic strategy utilizing endogenous NSCs for ischemic stroke.
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Affiliation(s)
- Fang Zhang
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Xiaohui Duan
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Liejing Lu
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Xiang Zhang
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Xiaomei Zhong
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Jiaji Mao
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Meiwei Chen
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
| | - Jun Shen
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong, China.
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21
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Tagge I, O’Connor A, Chaudhary P, Pollaro J, Berlow Y, Chalupsky M, Bourdette D, Woltjer R, Johnson M, Rooney W. Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model. PLoS One 2016; 11:e0152480. [PMID: 27054832 PMCID: PMC4824475 DOI: 10.1371/journal.pone.0152480] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 03/15/2016] [Indexed: 11/18/2022] Open
Abstract
Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100 μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.
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Affiliation(s)
- Ian Tagge
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
- Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Audrey O’Connor
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Priya Chaudhary
- Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Jim Pollaro
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Yosef Berlow
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Megan Chalupsky
- Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Dennis Bourdette
- Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
- Portland VA Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, United States of America
| | - Randy Woltjer
- Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
| | - Mac Johnson
- Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02210, United States of America
| | - William Rooney
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
- Biomedical Engineering, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
- Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America
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22
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Fricke IB, Viel T, Worlitzer MM, Collmann FM, Vrachimis A, Faust A, Wachsmuth L, Faber C, Dollé F, Kuhlmann MT, Schäfers K, Hermann S, Schwamborn JC, Jacobs AH. 6-hydroxydopamine-induced Parkinson's disease-like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging-detectable alteration in adult neurogenesis. Eur J Neurosci 2016; 43:1352-65. [PMID: 26950181 DOI: 10.1111/ejn.13232] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 03/03/2016] [Accepted: 03/04/2016] [Indexed: 12/22/2022]
Abstract
Parkinson's disease is a slowly progressing neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra (SN), leading to severe impairment in motor and non-motor functions. Endogenous subventricular zone (SVZ) neural stem cells constantly give birth to new cells that might serve as a possible source for regeneration in the adult brain. However, neurodegeneration is accompanied by neuroinflammation and dopamine depletion, potentially compromising regeneration. We therefore employed in vivo imaging methods to study striatal deafferentation (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[(123) I]iodophenyl)nortropane single photon emission computed tomography, DaTscan(™) ) and neuroinflammation in the SN and striatum (N,N-diethyl-2-(2-(4-(2-[(18) F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide positron emission tomography, [(18) F]DPA-714 PET) in the intranigral 6-hydroxydopamine Parkinson's disease mouse model. Additionally, we transduced cells in the SVZ with a lentivirus encoding firefly luciferase and followed migration of progenitor cells in the SVZ-olfactory bulb axis via bioluminescence imaging under disease and control conditions. We found that activation of microglia in the SN is an acute process accompanying the degeneration of dopaminergic cell bodies in the SN. Dopaminergic deafferentation of the striatum does not influence the generation of doublecortin-positive neuroblasts in the SVZ, but generates chronic astrogliosis in the nigrostriatal system.
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Affiliation(s)
- Inga B Fricke
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany.,ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, University of Münster, Münster, Germany
| | - Thomas Viel
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany
| | - Maik M Worlitzer
- ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, University of Münster, Münster, Germany
| | - Franziska M Collmann
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany
| | - Alexis Vrachimis
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany.,Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
| | - Andreas Faust
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany
| | - Lydia Wachsmuth
- Department of Clinical Radiology, University Hospital Münster, Münster, Germany
| | - Cornelius Faber
- Department of Clinical Radiology, University Hospital Münster, Münster, Germany.,DFG EXC 1003, Cluster of Excellence 'Cells in Motion', Münster, Germany
| | - Frédéric Dollé
- CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France
| | - Michael T Kuhlmann
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany
| | - Klaus Schäfers
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany.,DFG EXC 1003, Cluster of Excellence 'Cells in Motion', Münster, Germany
| | - Sven Hermann
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany.,DFG EXC 1003, Cluster of Excellence 'Cells in Motion', Münster, Germany
| | - Jens C Schwamborn
- ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, University of Münster, Münster, Germany.,Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-Belval, Luxembourg
| | - Andreas H Jacobs
- European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 15, D-48149, Münster, Germany.,DFG EXC 1003, Cluster of Excellence 'Cells in Motion', Münster, Germany.,Department of Geriatric Medicine, Evangelische Kliniken, Johanniter Krankenhaus, Bonn, Germany
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23
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Hoornaert CJ, Luyckx E, Reekmans K, Dhainaut M, Guglielmetti C, Le Blon D, Dooley D, Fransen E, Daans J, Verbeeck L, Quarta A, De Vocht N, Lemmens E, Goossens H, Van der Linden A, Roobrouck VD, Verfaillie C, Hendrix S, Moser M, Berneman ZN, Ponsaerts P. In Vivo Interleukin-13-Primed Macrophages Contribute to Reduced Alloantigen-Specific T Cell Activation and Prolong Immunological Survival of Allogeneic Mesenchymal Stem Cell Implants. Stem Cells 2016; 34:1971-84. [PMID: 26992046 DOI: 10.1002/stem.2360] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 02/12/2016] [Indexed: 12/11/2022]
Abstract
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue-for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins-is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since "off-the-shelf" cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated macrophage phenotype in vivo and a reduced number of alloantigen-reactive IFNγ- and/or IL2-producing CD8(+) T cells compared to nonmodified allografts. Similarly, intracerebral IL13-expressing MSC allografts also exhibited prolonged survival and induction of an alternatively activated macrophage phenotype, although a peripheral T cell component was absent. In summary, this study demonstrates that both innate and adaptive immune responses are effectively modulated in vivo by locally secreted IL13, ultimately resulting in prolonged MSC allograft survival in both muscle and brain tissue. Stem Cells 2016;34:1971-1984.
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Affiliation(s)
- Chloé J Hoornaert
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Evi Luyckx
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Kristien Reekmans
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Maxime Dhainaut
- Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium
| | | | - Debbie Le Blon
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Dearbhaile Dooley
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Erik Fransen
- StatUa Centre for Statistics, University of Antwerp, Antwerp, Belgium
| | - Jasmijn Daans
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Louca Verbeeck
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Alessandra Quarta
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Nathalie De Vocht
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Evi Lemmens
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Herman Goossens
- Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | | | - Valerie D Roobrouck
- Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium
| | - Catherine Verfaillie
- Stem Cell Institute, Stem Cell Biology and Embryology Unit, KU Leuven, Leuven, Belgium
| | - Sven Hendrix
- Department of Morphology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Muriel Moser
- Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium
| | - Zwi N Berneman
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.,Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
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24
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Aelvoet SA, Pascual-Brazo J, Libbrecht S, Reumers V, Gijsbers R, Van den Haute C, Baekelandt V. Long-Term Fate Mapping Using Conditional Lentiviral Vectors Reveals a Continuous Contribution of Radial Glia-Like Cells to Adult Hippocampal Neurogenesis in Mice. PLoS One 2015; 10:e0143772. [PMID: 26600383 PMCID: PMC4658138 DOI: 10.1371/journal.pone.0143772] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 11/09/2015] [Indexed: 11/21/2022] Open
Abstract
Newborn neurons are generated throughout life in two neurogenic regions, the subventricular zone and the hippocampal dentate gyrus. Stimulation of adult neurogenesis is considered as an attractive endogenous repair mechanism to treat different neurological disorders. Although tremendous progress has been made in our understanding of adult hippocampal neurogenesis, important questions remain unanswered, regarding the identity and the behavior of neural stem cells in the dentate gyrus. We previously showed that conditional Cre-Flex lentiviral vectors can be used to label neural stem cells in the subventricular zone and to track the migration of their progeny with non-invasive bioluminescence imaging. Here, we applied these Cre-Flex lentiviral vectors to study neurogenesis in the dentate gyrus with bioluminescence imaging and histological techniques. Stereotactic injection of the Cre-Flex vectors into the dentate gyrus of transgenic Nestin-Cre mice resulted in specific labeling of the nestin-positive neural stem cells. The labeled cell population could be detected with bioluminescence imaging until 9 months post injection, but no significant increase in the number of labeled cells over time was observed with this imaging technique. Nevertheless, the specific labeling of the nestin-positive neural stem cells, combined with histological analysis at different time points, allowed detailed analysis of their neurogenic potential. This long-term fate mapping revealed that a stable pool of labeled nestin-positive neural stem cells continuously contributes to the generation of newborn neurons in the mouse brain until 9 months post injection. In conclusion, the Cre-Flex technology is a valuable tool to address remaining questions regarding neural stem cell identity and behavior in the dentate gyrus.
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Affiliation(s)
- Sarah-Ann Aelvoet
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
| | - Jesus Pascual-Brazo
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
| | - Sarah Libbrecht
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
| | - Veerle Reumers
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
| | - Rik Gijsbers
- Leuven Viral Vector Core, KU Leuven, Leuven, Flanders, Belgium
| | - Chris Van den Haute
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium.,Leuven Viral Vector Core, KU Leuven, Leuven, Flanders, Belgium
| | - Veerle Baekelandt
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Leuven, Flanders, Belgium
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25
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Guglielmetti C, Veraart J, Roelant E, Mai Z, Daans J, Van Audekerke J, Naeyaert M, Vanhoutte G, Delgado Y Palacios R, Praet J, Fieremans E, Ponsaerts P, Sijbers J, Van der Linden A, Verhoye M. Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination. Neuroimage 2015; 125:363-377. [PMID: 26525654 DOI: 10.1016/j.neuroimage.2015.10.052] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/15/2015] [Accepted: 10/19/2015] [Indexed: 12/21/2022] Open
Abstract
Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.
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Affiliation(s)
- C Guglielmetti
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| | - J Veraart
- iMinds - Vision Lab, Department of Physics, University of Antwerp, Antwerp, Belgium; Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA
| | - E Roelant
- StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium
| | - Z Mai
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| | - J Daans
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | | | - M Naeyaert
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| | - G Vanhoutte
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| | | | - J Praet
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| | - E Fieremans
- Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA
| | - P Ponsaerts
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - J Sijbers
- iMinds - Vision Lab, Department of Physics, University of Antwerp, Antwerp, Belgium
| | | | - M Verhoye
- Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
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26
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Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P. Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 2015; 47:485-505. [PMID: 25445182 DOI: 10.1016/j.neubiorev.2014.10.004] [Citation(s) in RCA: 301] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 09/18/2014] [Accepted: 10/01/2014] [Indexed: 01/30/2023]
Abstract
The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following cuprizone treatment, and how these strengthened the cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.
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27
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Praet J, Santermans E, Daans J, Le Blon D, Hoornaert C, Goossens H, Hens N, Van Der Linden A, Berneman Z, Ponsaerts P. Early Inflammatory Responses following Cell Grafting in the CNS Trigger Activation of the Subventricular Zone: A Proposed Model of Sequential Cellular Events. Cell Transplant 2015; 24:1481-92. [DOI: 10.3727/096368914x682800] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
While multiple rodent preclinical studies, and to a lesser extent human clinical trials, claim the feasibility, safety, and potential clinical benefit of cell grafting in the central nervous system (CNS), currently only little convincing knowledge exists regarding the actual fate of the grafted cells and their effect on the surrounding environment (or vice versa). Our preceding studies already indicated that only a minor fraction of the initially grafted cell population survives the grafting process, while the surviving cell population becomes invaded by highly activated microglia/macrophages and surrounded by reactive astrogliosis. In the current study, we further elaborate on early cellular and inflammatory events following syngeneic grafting of eGFP mouse embryonic fibroblasts (mEFs) in the CNS of immunocompetent mice. Based on obtained quantitative histological data, we here propose a detailed mathematically derived working model that sequentially comprises hypoxia-induced apoptosis of grafted mEFs, neutrophil invasion, neoangiogenesis, microglia/macrophage recruitment, astrogliosis, and eventually survival of a limited number of grafted mEFs. Simultaneously, we observed that the cellular events following mEF grafting activates the subventricular zone neural stem and progenitor cell compartment. This proposed model therefore further contributes to our understanding of cell graft-induced cellular responses and will eventually allow for successful manipulation of this intervention.
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Affiliation(s)
- Jelle Praet
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
- BioImaging Laboratory, University of Antwerp, Wilrijk, Belgium
| | - Eva Santermans
- Center for Statistics, I-Biostat, Hasselt University, Diepenbeek, Belgium
| | - Jasmijn Daans
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Debbie Le Blon
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Chloé Hoornaert
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Herman Goossens
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Niel Hens
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
- Center for Statistics, I-Biostat, Hasselt University, Diepenbeek, Belgium
- Centre for Health Economic Research and Modeling Infectious Diseases (Chermid), University of Antwerp, Wilrijk, Belgium
| | | | - Zwi Berneman
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
| | - Peter Ponsaerts
- Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium
- Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Wilrijk, Belgium
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28
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Mayerl C, Baeckens S, Van Damme R. Evolution and role of the follicular epidermal gland system in non-ophidian squamates. AMPHIBIA-REPTILIA 2015. [DOI: 10.1163/15685381-00002995] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Many lizard and amphisbaenian lineages possess follicular glands in the dermis of the inner thighs and/or the area anterior to the cloaca. These tubular glands produce a holocrine secretion that finds its way to the external world through pore-bearing scales (femoral and/or preanal pores). Secretions are composed of proteins and many lipophilic compounds that may function as chemosignals in lizard and amphisbaenian communication. In recent years, we have begun to develop an understanding of the adaptive significance of these secretions, and they are currently thought to play an important role in a variety of processes in these animals. While it appears that epidermal gland secretions function in intra- and interspecific recognition and territoriality, research has focused largely on their role in mate assessment. Despite these recent studies, our knowledge on the true role of the chemicals found in epidermal secretions remains poorly studied, and there are many possible avenues for future research on this topic. Here, we review the literature on the follicular epidermal glands of non-ophidian squamates and provide a first taxon-wide overview of their distribution.
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Affiliation(s)
- Christopher Mayerl
- Clemson University, 132 Long Hall, Department of Biological Sciences, Clemson SC, 29634, USA
| | - Simon Baeckens
- University of Antwerp, Laboratory of Functional Morphology, Universiteitsplein 1 – C, 2610 Wilrijk, Belgium
| | - Raoul Van Damme
- University of Antwerp, Laboratory of Functional Morphology, Universiteitsplein 1 – C, 2610 Wilrijk, Belgium
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Haghmorad D, Mahmoudi MB, Mahmoudi M, Rab SZT, Rastin M, Shegarfi H, Azizi G, Mirshafiey A. Calcium intervention ameliorates experimental model of multiple sclerosis. Oman Med J 2014; 29:185-9. [PMID: 24936267 DOI: 10.5001/omj.2014.46] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 04/19/2014] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVE Multiple sclerosis (MS) is the most common inflammatory disease of the CNS. Experimental autoimmune encephalomyelitis (EAE) is a widely used model for MS. In the present research, our aim was to test the therapeutic efficacy of Calcium (Ca) in an experimental model of MS. METHODS In this study the experiment was done on C57BL/6 mice. EAE was induced using 200 μg of the MOG35-55 peptide emulsified in CFA and injected subcutaneously on day 0 over two flank areas. In addition, 250 ng of pertussis toxin was injected on days 0 and 2. In the treatment group, 30 mg/kg Ca was administered intraperitoneally four times at regular 48 hour intervals. The mice were sacrificed 21 days after EAE induction and blood samples were taken from their hearts. The brains of mice were removed for histological analysis and their isolated splenocytes were cultured. RESULTS Our results showed that treatment with Ca caused a significant reduction in the severity of the EAE. Histological analysis indicated that there was no plaque in brain sections of Ca treated group of mice whereas 4 ± 1 plaques were detected in brain sections of controls. The density of mononuclear infiltration in the CNS of Ca treated mice was lower than in controls. The serum level of Nitric Oxide in the treatment group was lower than in the control group but was not significant. Moreover, the levels of IFN-γ in cell culture supernatant of splenocytes in treated mice were significantly lower than in the control group. CONCLUSION The data indicates that Ca intervention can effectively attenuate EAE progression.
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Affiliation(s)
- Dariush Haghmorad
- Immunology Research Center, Buali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad B Mahmoudi
- Immunology Research Center, Buali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Genetics department, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Shahrzad Z T Rab
- Immunology Research Center, Buali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Rastin
- Immunology Research Center, Buali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Shegarfi
- Institute for Surgical Research, Oslo University Hospital HF, Oslo, Norway
| | - Gholamreza Azizi
- Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran-14155, Box: 6446, Iran
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Roose D, Leroux F, De Vocht N, Guglielmetti C, Pintelon I, Adriaensen D, Ponsaerts P, Van der Linden A, Bals S. Multimodal imaging of micron-sized iron oxide particles following in vitro and in vivo uptake by stem cells: down to the nanometer scale. CONTRAST MEDIA & MOLECULAR IMAGING 2014; 9:400-8. [PMID: 24753446 DOI: 10.1002/cmmi.1594] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 10/10/2013] [Accepted: 01/08/2014] [Indexed: 11/08/2022]
Abstract
In this study, the interaction between cells and micron-sized paramagnetic iron oxide (MPIO) particles was investigated by characterizing MPIO in their original state, and after cellular uptake in vitro as well as in vivo. Moreover, MPIO in the olfactory bulb were studied 9 months after injection. Using various imaging techniques, cell-MPIO interactions were investigated with increasing spatial resolution. Live cell confocal microscopy demonstrated that MPIO co-localize with lysosomes after in vitro cellular uptake. In more detail, a membrane surrounding the MPIO was observed by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). Following MPIO uptake in vivo, the same cell-MPIO interaction was observed by HAADF-STEM in the subventricular zone at 1 week and in the olfactory bulb at 9 months after MPIO injection. These findings provide proof for the current hypothesis that MPIO are internalized by the cell through endocytosis. The results also show MPIO are not biodegradable, even after 9 months in the brain. Moreover, they show the possibility of HAADF-STEM generating information on the labeled cell as well as on the MPIO. In summary, the methodology presented here provides a systematic route to investigate the interaction between cells and nanoparticles from the micrometer level down to the nanometer level and beyond.
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Affiliation(s)
- Dimitri Roose
- EMAT, University of Antwerp, Antwerp, Belgium; Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium; Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium
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