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      Stem Cell Tracking Technologies for Neurological Regenerative Medicine Purposes

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          Abstract

          The growing field of stem cell therapy is moving toward clinical trials in a variety of applications, particularly for neurological diseases. However, this translation of cell therapies into humans has prompted a need to create innovative and breakthrough methods for stem cell tracing, to explore the migration routes and its reciprocity with microenvironment targets in the body, to monitor and track the outcome after stem cell transplantation therapy, and to track the distribution and cell viability of transplanted cells noninvasively and longitudinally. Recently, a larger number of cell tracking methods in vivo were developed and applied in animals and humans, including magnetic resonance imaging, nuclear medicine imaging, and optical imaging. This review has been intended to summarize the current use of those imaging tools in tracking stem cells, detailing their main features and drawbacks, including image resolution, tissue penetrating depth, and biosafety aspects. Finally, we address that multimodality imaging method will be a more potential tracking tool in the future clinical application.

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          Manganese toxicity upon overexposure.

          Janelle Crossgrove, Wei. Zheng (2004)
          Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging. The administration of intravenous Mn impacts its homeostatic balance in the human body and can lead to toxicity. Human Mn deficiency has been reported in patients on parenteral nutrition and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder) and dietary overexposure and is evidenced primarily in the central nervous system, although lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results from an accumulation of the metal in brain tissue and results in a progressive disorder of the extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain Mn accumulation and neurotoxicity. The mechanism for the neurodegenerative damage specific to select brain regions is not clearly understood. Disturbances in iron homeostasis and the valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation therapy with EDTA and supplementation with levodopa are the current treatment options, which are mildly and transiently efficacious. In conclusion, repeated administration of Mn, or compounds that readily release Mn, may increase the risk of Mn-induced toxicity. Copyright 2004 John Wiley & Sons, Ltd.
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            Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury.

            Paul Lu, Grace Woodruff, Yaozhi Wang … (2014)
            Human induced pluripotent stem cells (iPSCs) from a healthy 86-year-old male were differentiated into neural stem cells and grafted into adult immunodeficient rats after spinal cord injury. Three months after C5 lateral hemisections, iPSCs survived and differentiated into neurons and glia and extended tens of thousands of axons from the lesion site over virtually the entire length of the rat CNS. These iPSC-derived axons extended through adult white matter of the injured spinal cord, frequently penetrating gray matter and forming synapses with rat neurons. In turn, host supraspinal motor axons penetrated human iPSC grafts and formed synapses. These findings indicate that intrinsic neuronal mechanisms readily overcome the inhibitory milieu of the adult injured spinal cord to extend many axons over very long distances; these capabilities persist even in neurons reprogrammed from very aged human cells.
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              Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo

              Bo Zheng, Marc P. von See, Elaine Yu … (2016)
              Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R2 = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents.
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                Author and article information

                Contributors
                Jianhong Zhu:
                ORCID: http://orcid.org/0000-0001-9004-651X
                Journal
                Journal ID (nlm-ta): Stem Cells Int
                Journal ID (iso-abbrev): Stem Cells Int
                Journal ID (publisher-id): SCI
                Title: Stem Cells International
                Publisher: Hindawi
                ISSN (Print): 1687-966X
                ISSN (Electronic): 1687-9678
                Publication date (Print): 2017
                Publication date (Electronic): 12 September 2017
                Volume: 2017
                Electronic Location Identifier: 2934149
                Affiliations
                1Department of Neurosurgery, Fudan University Huashan Hospital, National Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200040, China
                2Department of Urinary Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
                Author notes

                Academic Editor: Yao Li

                Author information
                http://orcid.org/0000-0001-9004-651X
                Article
                DOI: 10.1155/2017/2934149
                PMC ID: 5613625
                PubMed ID: 29138636
                SO-VID: a86e16bd-2270-4a27-9176-a4ae077a3176
                Copyright © Copyright © 2017 Yongtao Zheng et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 25 February 2017
                Date revision received : 12 June 2017
                Date accepted : 9 July 2017
                Funding
                Funded by: Ministry of Science and Technology of the People's Republic of China
                Funded by: National Nature Science Foundation
                Award ID: ZJ2014-ZD-002
                Award ID: 81271003
                Award ID: 2012CB966300
                Award ID: 2013CB967400
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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