Printer Friendly

Potential Therapeutic Mechanisms and Tracking of Transplanted Stem Cells: Implications for Stroke Treatment.

1. Introduction

Stroke is a leading cause of death and long-term disability worldwide [1-5], and current epidemiological data suggest that the economic and social burdens of this disease will progressively increase over the next few decades. Approximately 795,000 individuals in the United States experience a stroke from 2003 to 2013 [6, 7]. Pathological subtypes comprise ischemic stroke and hemorrhagic stroke [8, 9]. In the Western world, ischemic stroke accounts for 87% of all stroke cases, and the remainder are hemorrhagic (intracerebral hemorrhage and subarachnoid hemorrhage) [6]. In ischemic stroke, an embolus or thrombus occludes a blood vessel, causing a reduction in blood blow to the brain and triggering a cascade of pathological responses associated with energy failure, excessive intracellular calcium, excessive excitatory amino acid release, the generation of reactive free oxygen species, and inflammation, ultimately causing irreversible brain impairment [10-12]. In the present study, numerous experiment animal models are used for the study of ischemic stroke, which are mainly divided into two broad categories: focal and global ischemia [13]. Focal ischemia is commonly used in basic research to mimic human stroke condition, which can be classified as transient or permanent occlusions. Among them, the middle cerebral artery occlusion (MCAO) model is widely accepted. Thread embolism is advanced through the external carotid artery to block the MCA resulting in consequent ischemic damage mainly in the corpus striatum and cortex brain regions [14].

To date, intravenous tissue plasminogen activator (tPA), which is only administered within 4.5 h of ischemic stroke, is effective [8, 15]. For patients who are unable to be treated within that therapeutic window, tPA is largely inadequate. Additionally, intravenous tPA enhances the risk of cerebral hemorrhage which limits its clinical application [16]. In recent year, another promising strategy for treatment of acute ischemic stroke is endovascular blood clot removal in large cerebral arteries with a stent retrieve [17, 18].

Numerous randomized trials have suggested that patients with a proximal cerebral arterial occlusion treated with rapid endovascular treatment could improve reperfusion and functional neurologic outcomes better than systemic tPA [19-21]. Numerous neuroprotective drugs targeting excitotoxicity, inflammation, or oxidative stress have proven unsuccessful [12, 22]. Conversely, emerging evidence indicates that stem cells may be a promising therapeutic avenue for cerebral ischemia. Stem cells possess self-renewal and multidirectional differentiation abilities [23]. At present, different types of stem cells are under investigation to determine their efficacy for the treatment of stroke, including mesenchymal stem cells (MSCs) [24], human umbilical cord blood mononuclear cells [25], neural stem cells (NSCs) [26], and adipose-derived progenitor cells [27]. Stem cell therapy has received considerable attention and is under extensive study, but the precise stem cell-mediated mechanisms governing improved outcomes after stroke remain unclear. Preclinical data suggest that stem cell therapy is a promising regenerative medical treatment given the limited capacity of the central nervous system (CNS) for self-repairs after ischemic stroke. Stem cells appear to release neurotrophic and growth factors to induce innate repair mechanisms, such as angiogenesis and neurogenesis [28, 29], in the adult brain and modulate the inflammatory response [30]. Additionally, stem cells secrete exosomes, which cross the blood-brain barrier (BBB) [31] to transfer certain proteins, noncoding RNA, and lipids to regulate recipient cells [32-34].

It is important to observe the survival, migration, distribution, and clearance of implanted stem cells to better understand their therapeutic mechanisms. In vivo imaging modalities for cell tracking are crucial tools for the development and optimization of stem cell therapy. Optical imaging, magnetic resonance imaging (MRI), magnetic particle imaging (MPI), and nuclear imaging, including single photon emission computerized tomography (SPECT) and positron emission tomography (PET), are generally used for cell tracking. Tracker agents must be safe, nontoxic, and biocompatible in clinical trials. Nanoparticles, particularly those labeled with superparamagnetic iron oxide (SPIO), are widely used in preclinical and clinical trials [35-37]. SPIO-labeled cells are tracked using MRI or MPI. SPECT and PET are used to track cells labeled with radioisotopes such as In-111-oxine [38] and [sup.125]iodine [39].

To further enhance the therapeutic effects of stem cells for the treatment of stroke and to determine an optimized therapeutic strategy, proper methods for cell labeling and appropriate imaging modalities must be employed. In this review, the potential therapeutic mechanisms of stem cell transplantation for the treatment of stroke and the limitations of current therapies will be discussed. We will also discuss methods for labeling transplanted cells and existing imaging systems for stem cell labeling and tracking in vivo.

2. Mechanisms of Stem Cell Transplantation to Treat Ischemic Stroke

2.1. Cell Replacement and Differentiation. Stem cell differentiation and appropriate incorporation into the existing neural network to replace the functions of lost neurons after transplantation represent critical aspects of cell-based therapy. Accumulating evidence suggests that transplanted stem cells have the ability to replace lost neurons via migration to damaged regions and promote neural differentiation, which contributes to behavioral improvements in different stroke models [40, 41]. Choi et al. [42] transplanted human bone marrow-derived mesenchymal stem cells (BM-MSCs) after photothrombotic ischemia and observed the elevated expression of neural and synaptic-relative proteins; additionally, the cells not only integrated well into the existing host circuitry but also enhanced endogenous neural differentiation in MSC-treated groups. At 7 days after transplantation, significant behavioral improvements appeared in the BMMSC-treated group. Another study reported the utility of transplanting human embryonic stem cell- (hESC-) derived neural precursor cells (hNPCs) into the cortex to replace dying brain cells after permanent distal middle cerebral artery occlusion in rats, resulting in improved functional outcomes. The majority of transplanted hNPCs were positive for nestin, a marker of neural precursor cells. Approximately 10% of the cells differentiated into neuronal phenotypes 2 months after transplantation, and very few cells expressed astroglial or oligodendrocyte markers [43]. Other preclinical studies have reported the ability of NSCs from the human fetal striatum and cortex to survive, migrate, and differentiate into neurons in the stroke-damaged rat striatum [44]. Furthermore, homogenous populations of human neural stem cells (hNSCs) not only possess a remarkable ability to migrate into damaged regions and differentiate into neurons, astrocytes, and oligodendrocytes but also exhibit lower tumorigenicity in vivo [45]. Cheng et al. demonstrated the ability of intravenously delivered NSCs to traverse the BBB and migrate into the ischemic brain. Approximately 86% of transplanted NSCs maintained proliferative capability and enhanced the proliferation of endogenous cells. The intravenous administration of NSCs 24 h after stroke significantly improves functional deficits, but a reduction in cerebral infraction volume was not detected by TTC staining [46].

2.2. Endogenous Repair Mechanisms. Mounting evidence indicates that implanted stem cells accelerate long-term functional recovery by migrating toward the ischemic zone to enhance endogenous repair mechanisms via the secretion of growth factors [47, 48]. The adult mammalian brain contains a population of NSCs in the subventricular zone (SVZ) of the lateral ventricle that migrates to the olfactory bulb and generates new neurons [49, 50] and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) [51, 52]. Brain injury, such as stroke, induces neurogenesis and angiogenesis [53-55] and promotes the proliferation and migration of neuroblasts or neural progenitor cells derived from the SVZ toward the injured site [56-58]. Angiogenesis is observed immediately after stroke because new blood vessels significantly increase by 3 days postinjury, and the proliferation of endothelial cells increases as early as 1 day postinjury [59]. Under ischemic conditions, SVZ multipotent NSCs derived from the stroke-injured cortex are capable of neurosphere formation and give rise to a subpopulation of reactive astrocytes in the cortex that contribute to astrogliosis and scar formation. Expression of the transcription factor Ascl1 converts SVZ-derived reactive astrocytes into neurons in vivo [60]. However, the brain possesses a limited ability to form new neurons after injury, and endogenous regeneration mechanisms are insufficient to replace lost neurons [58]. Thus, there is a need to develop novel methods to enhance stroke-induced neurogenesis. Chromatin-modifying agents, which have previously been used as novel biological probes as well as for the treatment of cerebral ischemia, represent a viable method to stimulate endogenous NSCs and enhance NSC-mediated endogenous brain repair mechanisms [61]. Interestingly, channelrhodopsin-2 (ChR2) transgenic mice that undergo the optogenetic stimulation of glutamatergic activity in the striatum after stroke release glutamate into the SVZ, causing SVZ neuroblast proliferation and migration to the peri-infarct cortex via activation of the AMPA receptor. The stimulation of striatal glutamatergic activity may increase the survival and neuronal differentiation of recruited neuroblasts, thus improving functional recovery [62].

2.3. Secretion of Trophic Factors and Regulation of the Ischemic Microenvironment. Stem cells may regulate the neurovascular microenvironment to promote tissue repair and regeneration via autocrine or paracrine activity involving the release of cytokines, growth factors, or secreted extracellular vesicles. A recent study demonstrated the ability of extracellular vesicles released from stem cells to elicit biological functions similar to the stem cells themselves [63, 64], which represents a novel mechanism of intercellular communication, by delivering their cargo consisting of synaptic proteins, noncoding RNA, DNA, and lipids to acceptor cells, thus altering their gene expression under physiological and pathophysiological conditions [65-68]. Extracellular vesicles primarily include exosomes and microvesicles [69]. Exosomes are small (30-100 nm) membrane vesicles formed by the fusion of multivesicular bodies (MVBs) with the cell plasma membrane, are secreted by diverse cell types, and are present in body fluid such as blood, saliva, urine, and cerebrospinal fluid (CSF) [70, 71]. Exosomes are involved in cell communication, migration, angiogenesis, and cell growth processes in tumors and are considered natural carriers for applications in clinical trials. The systemic administration of exosomes released from mesenchymal stromal cells resulted in significant functional enhancement in the footfault test and a modified neurological severity score starting 2 weeks after treatment, as well as increased neurite remodeling, neurogenesis, and angiogenesis in the ischemic boundary zone after stroke in rats [72]. Further study demonstrated that exosomes harvested from microRNA 133b-overexpressing multipotent mesenchymal stromal cells improved neurological outcomes post-MCAO in rats beyond those elicited by naive exosomes because the exosomes indirectly downregulated the expression of Rab9 effector protein with kelch motifs (RABEPK) to further stimulate the release of exosomes from cultured primary astrocytes and then promote neurite outgrowth and elongation in vitro [73]. MRI suggested that the intravenous injection of xenogenic (from minipig) adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes reduced brain infarct size 28 days after acute ischemic stroke, and neurological function underwent a significant improvement on day 14 following stroke. Moreover, in the xenogenic ADMSC/ADMSC-derived exosome treatment group, immune reactions and damage to major organs (brain, heart, lung, liver, and kidney) were not observed [74]. Exosomes generated from glioma stem cells promote the angiogenic capacity of endothelial cells by transferring miR-21 to downregulate the expression of vascular endothelial growth factor (VEGF) [32]. Stem cells enhance the endogenous repair capacity of the brain [32] and attenuate inflammatory reactions [75] though the secretion of trophic or growth factors. The majority of transplanted brain-derived neurotrophic factor- (BDNF-) overexpressing human NSCs express C-X-C chemokine receptor 4 (CXCR4), a chemokine receptor that is associated with inflammation [76]. Pretreatment of NSCs with BDNF causes the secretion of VEGF and macrophage colony-stimulating factor (M-CSF), CXCR4, and vascular cell adhesion molecule-1 (VCAM-1) expression and differentiation into mature neurons [77].

2.4. Alleviation of the Inflammatory Response. It is critical to alleviate the inflammatory response given its contribution to secondary brain injury after cerebral ischemia and experimental subarachnoid hemorrhage (eSAH) [78]. During cerebral ischemia, damaged tissue releases damage-associated molecular patterns (DAMPs) [79], which lead to a series of inflammatory responses such as the activation of microglia and the production of proinflammatory factors, followed by neutrophil recruitment and infiltration, which increase the permeability of the BBB [80, 81] and activate the complement system [82]. A variety of inflammatory factors regulate inflammation in the brain, such as tumor necrosis factor (TNF-[alpha]) and interleukin 1 (IL-1). MSCs possess the ability to orchestrate other cells to exert anti-inflammatory effects. Microglia cells incubated with IL-1-primed MSC conditioned medium increase their expression of anti-inflammatory, neurotrophic mediators and decrease their secretion of inflammatory markers such as interleukin 6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and TNF-[alpha] [30]. MSCs and extracellular vesicles derived from MSCs intravenously injected after focal cerebral ischemia in mice were shown to modulate immune responses and attenuate postischemic immunosuppression in the peripheral blood [64]. Hypoxia-inducible factor 1-[alpha]- (Hif-1[alpha]-) modified MSCs implanted in a rat MCAO stroke model promote neurotrophin secretion while inhibiting the generation of proinflammatory cytokines [83]. According to Shichita et al., the efficient internalization of DAMPs, such as high-mobility-group box 1 (HMGB1), peroxiredoxins (PRXs), S100A8, and S100A9, is mediated by macrophage scavenger receptor 1 (MSR1) and macrophage receptor with collagenous structure (MARCO) in a murine model of ischemic stroke. Musculoaponeurotic fibrosarcoma bZIP transcription factor B (MAFB), a critical modulator of myeloid cell differentiation and proliferation [84, 85], enhances the expression of MSR1 in infiltrating myeloid cells. MSR1, MARCO, and MAFB deficiency causes the impaired clearance of DAMPs with consequent severe inflammation and neuronal injury [86].

2.5. Neuroprotective Effects and the Promotion of Axon Growth. Occlusion of a blood vessel by an embolus or thrombus causes a reduction in blood flow to the brain, which induces the disruption of the mitochondrial electron transport chain and the failure of oxidative phosphorylation. ATP supply fails, and excessive intracellular calcium is present in cells, ultimately causing neuronal damage [87]. Spermine and spermidine, which are free radical scavengers, have the ability to reduce lipid peroxidation [88] and modulate ion channels, receptor, and calcium trafficking [89]. In ischemic stroke, spermine significantly reduces infarction and neurological deficit [90]. Human mesenchymal stem cell treatment has a limited ability to restore cellular polyamine homeostasis, while levels of its metabolic products putrescine and spermidine significantly increase [91]. After CNS injuries such as ischemia and trauma, energy failure causing intracellular signaling disruption and several deleterious cascades are activated resulting in axonal degeneration and neuron death [92, 93]. In one systemic study, miR-133b overexpression in multipotent MSCs was systemically induced in rats subjected to MCAO. MiR-133b released from MSCs was transferred into astrocytes and neurons via exosomes both in vitro and in vivo, thus regulating connective tissue growth factor (CTGF) and ras homolog gene family member A (RhoA) expression and increasing axonal plasticity and neurite remodeling in the ischemic boundary zone (IBZ), subsequently promoting functional recovery after stroke [94, 95]. The transplantation of human neural progenitor cells 1 week after stroke significantly increases dendritic plasticity, promotes axonal rewiring, reduces the impairment of axonal transport, and enhances stem cell-induced functional recovery [47].

3. Limitations of Stem Cell Therapies

The clinical effectiveness of stem cell therapy is controversial, although accumulating evidence suggests that stem cell therapy has the potential to improve behavior and neurological function after experimental cerebral ischemia. Steinberg et al. [96] stereotactically implanted modified BM-MSCs into the brains of 18 patients with stroke. The surgical procedure and cell treatment were generally safe, and a significant improvement in neurological function was achieved after 12 months, which is consistent with a meta-analysis of preclinical studies indicating that stereotactic intracranial administration of MSCs significantly improves stroke outcomes [97]. Furthermore, human neuronal cells intracerebrally implanted into stroke patients with subcortical motor deficits measurably improved function in some patients, although a significant benefit in motor function was not observed [98]. A phase 2 trial comprising 58 patients with subacute ischemic stroke reported the safety of the intravenous administration of autologous bone marrow-derived mononuclear cells, but no beneficial improvements to neurological function were observed [99]. Another clinical trial suggested that the intra-arterial infusion of autologous bone marrow mononuclear stem cells results in minimal adverse reactions and may improve locomotion and language skills and decrease infarction volume, although these benefits were not significant compared with the nontreated group [100].

Stem cells represent an effective strategy to treat brain injury, but the precise mechanisms underlying stem cell therapy remain elusive due to the lack of appropriate cell tracking technology. Furthermore, the cell type, timing, dosage, and route of administration as well as the safety and biocompatibility of the tracker agents must all be considered. Stem cell therapy for the treatment of stroke improves functional recovery and offers the benefit of extending the intervention window via both intracerebral/intracranial (IC) transplantation and peripheral implantation routes, such as intravenous (IV), intra-arterial (IA), and intranasal administration [101]. IC transplantation is a more invasive procedure that allows precise injection into a chosen location, such as the penumbra and the ischemic core, to guarantee minimal cell delivery to untargeted areas [102, 103]. IV and IA systemic administration are less invasive and convenient approaches that results in the wide distribution of injected cells, but very low levels of cells migrate to the site of injury [38, 104]. Intranasal delivery of stem cells is noninvasive and targets the brain [105, 106]. Different administration routes cause the differential biodistribution of transplanted cells, although all routes improve functional recovery of the brain. Thus, it is critical to understand the homing of transplanted stem cells to sites of injury and to monitor transplant dynamic processes, including cell proliferation, migration, and biodistribution. To obtain optimal therapeutic effects and enhance our understanding of the mechanism by which stem cells promote functional recovery in neurological disorders, it is essential to develop noninvasive, reproducible, and quantitative in vivo imaging approaches to track stem cell fate. In recent year, the methods for in vivo labeling and tracking of implanted stem cells consist of MRI [39, 107], optical imaging (fluorescence and bioluminescence imaging) [108, 109], and nuclear imaging including SPECT [110] and PET [111].

4. In Vivo Imaging Systems and Tracker Agents for Transplanted Stem Cells

4.1. SPIO Nanoparticles. Extensive work has been done to synthesize and make surface modifications to SPIOs. Iron oxide nanoparticles are roughly divided into SPIO, ultrasmall SPIO (USPIO), monocrystalline iron oxide nanoparticles (MION), and micron-sized superparamagnetic iron oxide (MPIOs) based on size. SPIO contrast agents are particles composed of an iron-oxide core coated with dextran (ferumoxide) or carboxydextran (ferucarbotran) [112] and protamine sulfate (Pro), which are FDA-approved agents. SPIO nanoparticles are capable of labeling the vast majority of mammalian cells and are imageable during animal experiments and clinical trials. MRI is used to determine the homing, migration, and differentiation of stem cells labeled with SPIO [113, 114]. This image modality possesses high spatial resolution, which facilitates long-term and single-cell detection, and is noninvasive and utilizes nonionizing radiation. Cells labeled with SPIO exhibit low-intensity signals during T2 and [T2.sup.*] MRI imaging [113, 115]. MION labels stem cells without requiring the use of a transfection agent [116] and does not affect cell viability, phenotype, and in vitro differentiation capacity [112]. Many measures have been taken to improve labeling efficiency and enhance MRI detection sensitivity. Compounding fluorescent mesoporous silica-coated SPIO for stem cell MRI is used to enhance the detection sensitivity and efficiency for cell labeling with no adverse reactions [117, 118]. It is also useful to combine MRI with other noninvasive imaging modalities such as reporter gene-based molecular techniques to overcome any deficiencies and obtain more information on the behavior of implanted cells. hNSCs stably expressing enhanced green fluorescence protein (eGFP) and firefly luciferase (fLuc) reporter genes were labeled with SPIO for MRI and grafted into an experimental stroke model. The survival, tumorigenicity, and immunogenicity of grafted cells were efficiently tracked in real time and investigated for 2 months using multimodal MRI and bioluminescence imaging (BLI) techniques [41]. MSCs labeled with SPIO synthesized in the laboratory were intra-arterially injected in a canine stroke model, given its similarity to the human brain, and were tracked using in vivo 3.0 T MRI imaging for at least four weeks [119]. SPIO (448 [micro]g/mL) had no adverse effects on the viability of adipose-derived canine MSCs [120]. However, exact cell quantification using an MRI imaging system may result in errors because MRI possesses large background signals from subject interfaces, and certain pathological conditions such as hemorrhage cause similar MRI signals, resulting in mistakes during the measurement of iron-containing contrast agent accumulation.

Magnetic particle imaging (MPI) is a novel molecular imaging technique that is limited to magnetic tracers and directly images SPIO nanoparticle-tagged cells [121, 122]. SPIO tracers introduced into the body generate MPI signals, while animals themselves neither generate nor reduce MPI signals [123, 124]. Thus, MPI provides accurate quantification, high image contrast, and longitudinal observation to monitor the distribution and location of stem cells. MPI is very suitable for preclinical and clinical applications to evaluate functional brain physiology during pulmonary perfusion [125] and traumatic brain injury [126], and there are few background tissue signals using optimized long-circulation SPIO trackers [127]. MPI is applicable to track transplanted cell redistribution and localization in vivo. In a recent study, the intravenous administration and dynamic distribution of SPIO-labeled MSCs in rats were monitored using MPI. Tracer clearance from the body can also be quantified using longitudinal MPI [128]. In other studies, MPI is able to track the long-term fate of exogenously labeled human stem cells with high image contrast in the murine brain and whole body for weeks to months [129].

4.2. Radiopharmaceuticals. Cells labeled with radioisotopes are generally tracked more accurately using SPECT and PET given their extraordinary sensitivity and tissue penetration, minimal background signals, and capacity to scan an entire body to investigate cell distribution to other organs. Radiotracers lacking toxicity and effects on cell viability are urgently needed. [sup.111]In causes damage to labeled cells due to its radioactivity and toxicity, although it has a half-life of 67 h, thus allowing long-term monitoring of up to 14 days [130, 131]. Cells labeled with indium-111-oxine exert low negative effects on cell viability [38]. However, the radioactive decay of usable tracers is not suitable for long-term tracking and limits the development of nuclear medicine techniques. Radioactive technetium-99m ([sup.99m]Tc) and [sup.18]F-fluorideoxyglucose ([sup.18]FDG), a glucose analogue, are not suitable for long-term monitoring due to their short half-lives. It is necessary to combine two imaging modalities to address this defect. In recent study, an MRI/SPECT/ fluorescent tri-modal probe ([sup.125]I-fSi[O.sub.4]@SPIOs) was synthesized by labeling fluorescent silica-coated SPIO with [sup.125]iodine to quantitatively track MSCs transplanted intracerebrally or intravenously into stroke rats, and the therapeutic efficacy of different injection routes and possible therapeutic mechanisms were evaluated. Neurobehavioral outcomes were significantly improved due to the upregulation of VEGF, basic fibroblast growth factor (bFGF), and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), although IC-infused MSCs migrated to the lesion site along the corpus callosum and IV-injected MSCs were primarily entrapped in the lung [39].

4.3. Fluorophore and Reporter Gene Expression Labeling Techniques. Optical imaging systems incorporating fluorescent imaging (FLI) and bioluminescence imaging (BLI) are used for whole-body imaging but with lower resolution and sensitivity. Fluorescent nanoparticles are suitable for stem cell long-term monitoring [132] and do not affect cell viability and proliferation. Luciferase produces a natural form of chemiluminescence during substrate oxidation. Stem cells transfected with the luciferase reporter gene are detectable using BLI, which is both noninvasive and quantitative. In one study, endothelial colony-forming cells (ECFC) were infected with a lentivirus containing eGFP and fLuc grafted into a photothrombotic (PT) stroke model. Strong BLI signals suggested that ECFCs migrate into the ischemic region [133]; overall, it was possible to monitor endogenous neural stem cells (eNSCs) in a PT stroke model using BLI in vivo. The stereotactic injection of conditional lentiviral vectors (Cre-Flex LVs) encoding fLuc and eGFP in the SVZ of nestin-Cre transgenic mice generates specifically labeled eNSCs. This results in significant increases in BLI signals, indicating the proliferation of eNSCs. Additionally, BLI signals relocalize from the SVZ toward the infarct region during the 2 weeks following stroke, demonstrating that nestin-positive eNSCs originating from the SVZ promote proliferation, migration toward the infarct region, and differentiation into both astrocytes and neurons during ischemic stroke [134]. In another study, labeled umbilical cord-derived mesenchymal stem cells (UMSCs) with multigold nanorod (multi-GNR) crystal-seeded magnetic mesoporous silica nanobeads (GRMNBs) were further transfected with lentivirus-luciferase protein (Luc-GRMNBs-UMSC). Photoacoustic PA signals suggested Luc-GRMNBs-UMSC homing to the infarcted area with the aid of a magnet and 7T MRI were suitable for the long-time tracking of transplanted stem cells. MRI revealed multiple low signals located inside the damage site, indicating Luc-GRMNBs-UMSCs migrated to the stroke region [135]. It is necessary to understand the primary distribution and homing of eNSCs in vivo because stroke affects neurogenesis in the adult mammalian brain.

Recent studies investigating tracer agents that are currently available for stem cell tracking in stroke are displayed in Table 1.

5. Conclusion

Several preclinical and clinical trials have shown that stem cell therapy for cerebral ischemia is safe and feasible and has the ability to promote neurologic functional recovery. However, the precise mechanisms underlying the benefits of stem cell transplantation have not yet been fully elucidated. To achieve optimal therapeutic effects and enhance our understanding of the mechanisms by which stem cells promote functional recovery in neurological disorders, it is essential that we develop noninvasive, reproducible, and quantitative in vivo imaging approaches to track stem cell fate. Additionally, the combination of different labeling agents facilitates better and long-term stem cell tracking in vivo with appropriate safety and feasibility. Each imaging modality has advantages and disadvantages, and the combined use of different imaging modalities strengthens their respective advantages, allowing us to gain a better understanding of the homing, distribution, and differentiation of implanted cells in vivo.

https://doi.org/ 10.1155/2017/2707082

Conflicts of Interest

The authors declare no potential conflict of interests.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (no. 2017YFA0104303, no. 81473190, no. 81673410, and no. 81603090).

References

[1] X. Hu, T. M. De Silva, J. Chen, and F. M. Faraci, "Cerebral vascular disease and neurovascular injury in ischemic stroke," Circulation Research, vol. 120, no. 3, pp. 449-471, 2017.

[2] S. A. Acosta, N. Tajiri, J. Hoover, Y. Kaneko, and C. V. Borlongan, "Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke," Stroke, vol. 46, no. 9, pp. 2616-2627,2015.

[3] S. Baltan, R. S. Morrison, and S. P. Murphy, "Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury," Neurotherapeutics, vol. 10, no. 4, pp. 798-807, 2013.

[4] F. Denorme and S. F. De Meyer, "The VWF-GPIb axis in ischaemic stroke: lessons from animal models," Thrombosis and Haemostasis, vol. 116, no. 4, pp. 597-604, 2016.

[5] R. Vemuganti, "All's well that transcribes well: non-coding RNAs and post-stroke brain damage," Neurochemistry International, vol. 63, no. 5, pp. 438-449, 2013.

[6] E. J. Benjamin, M. J. Blaha, S. E. Chiuve et al., "Heart disease and stroke statistics-2017 update: a report from the American Heart Association," Circulation, vol. 135, no. 10, pp. e146-e603, 2017.

[7] Writing Group Members, D. Mozaffarian, E. J. Benjamin et al., "Executive summary: heart disease and stroke statistics--2016 update: a report from the American Heart Association," Circulation, vol. 133, no. 4, pp. 447-454, 2016.

[8] G. J. Hankey, "Stroke," Lancet, vol. 389, no. 10069, pp. 641-654, 2017.

[9] N. R. Sims and H. Muyderman, "Mitochondria, oxidative metabolism and cell death in stroke," Biochimica et Biophysica Acta, vol. 1802, no. 1, pp. 80-91, 2010.

[10] J. Puyal, V. Ginet, and P. G. Clarke, "Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection," Progress in Neurobiology, vol. 105, pp. 24-48, 2013.

[11] K. Szigeti, I. Horvath, D. S. Veres et al., "A novel SPECT-based approach reveals early mechanisms of central and peripheral inflammation after cerebral ischemia," Journal of Cerebral Blood Flow and Metabolism, vol. 35, no. 12, pp. 1921-1929, 2015.

[12] A. Chamorro, U. Dirnagl, X. Urra, and A. M. Planas, "Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation," Lancet Neurology, vol. 15, no. 8, pp. 869-881, 2016.

[13] L. Wei, Z. Z. Wei, M. Q. Jiang, O. Mohamad, and S. P. Yu, "Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke," Progress in Neurobiology, 2017.

[14] A. Durukan and T. Tatlisumak, "Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia," Pharmacology, Biochemistry, and Behavior, vol. 87, no. 1, pp. 179-197, 2007.

[15] R. Morihara, S. Kono, K. Sato et al., "Thrombolysis with low-dose tissue plasminogen activator 3-4.5 h after acute ischemic stroke in five hospital groups in Japan," Translational Stroke Research, vol. 7, no. 2, pp. 111-119, 2016.

[16] H. Liu, Y. Wang, Y. Xiao, Z. Hua, J. Cheng, and J. Jia, "Hydrogen sulfide attenuates tissue plasminogen activator-induced cerebral hemorrhage following experimental stroke," Translational Stroke Research, vol. 7, no. 3, pp. 209-219, 2016.

[17] M. G. Hennerici, "Is there a new era for stroke therapy?" Cerebrovascular Diseases, vol. 40, no. 1-2, pp. I-II, 2015.

[18] M. Reinhard, C. A. Taschner, N. Horsch et al., "Endovascular treatment versus sonothrombolysis for acute ischemic stroke," Cerebrovascular Diseases, vol. 40, no. 5-6, pp. 205-214, 2015.

[19] B. C. Campbell, P. J. Mitchell, T. J. Kleinig et al., "Endovascular therapy for ischemic stroke with perfusion-imaging selection," The New England Journal of Medicine, vol. 372, no. 11, pp. 1009-1018, 2015.

[20] M. Goyal, A. M. Demchuk, B. K. Menon et al., "Randomized assessment of rapid endovascular treatment of ischemic stroke," The New England Journal of Medicine, vol. 372, no. 11, pp. 1019-1030, 2015.

[21] O. A. Berkhemer, P. S. Fransen, D. Beumer et al., "A randomized trial of intraarterial treatment for acute ischemic stroke," The New England Journal of Medicine, vol. 372, no. 1, pp. 11-20, 2015.

[22] Q. Alhadidi, M. S. Bin Sayeed, and Z. A. Shah, "Cofilin as a promising therapeutic target for ischemic and hemorrhagic stroke," Translational Stroke Research, vol. 7, no. 1, pp. 33-41,2016.

[23] J. Wu and J. C. Izpisua Belmonte, "Stem cells: a renaissance in human biology research," Cell, vol. 165, no. 7, pp. 1572-1585, 2016.

[24] H. Zhang, F. Sun, J. Wang et al., "Combining injectable plasma scaffold with mesenchymal stem/stromal cells for repairing infarct cavity after ischemic stroke," Aging and Disease, vol. 8, no. 2, pp. 203-214, 2017.

[25] L. Huang, Y. Liu, J. Lu, B. Cerqueira, V. Misra, and T. Q. Duong, "Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function," Stem Cell Research & Therapy, vol. 8, no. 1, p. 74, 2017.

[26] J. D. Bernstock, L. Peruzzotti-Jametti, D. Ye et al., "Neural stem cell transplantation in ischemic stroke: a role for preconditioning and cellular engineering," Journal of Cerebral Blood Flow and Metabolism, vol. 37, no. 7, pp. 2314-2319, 2017.

[27] K. Zhao, R. Li, C. Gu et al., "Intravenous administration of adipose-derived stem cell protein extracts improves neurological deficits in a rat model of stroke," Stem Cells International, vol. 2017, Article ID 2153629, 11 pages, 2017.

[28] M. Uemura, Y. Kasahara, K. Nagatsuka, and A. Taguchi, "Cell-based therapy to promote angiogenesis in the brain following ischemic damage," Current Vascular Pharmacology, vol. 10, no. 3, pp. 285-288, 2012.

[29] H. J. Lee, I. J. Lim, M. C. Lee, and S. U. Kim, "Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model," Journal of Neuroscience Research, vol. 88, no. 15, pp. 3282-3294, 2010.

[30] E. Redondo-Castro, C. Cunningham, J. Miller et al., "Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro," Stem Cell Research & Therapy, vol. 8, no. 1, p. 79, 2017.

[31] C. C. Chen, L. Liu, F. Ma et al., "Elucidation of exosome migration across the blood-brain barrier model in vitro," Cellular and Molecular Bioengineering, vol. 9, no. 4, pp. 509-529, 2016.

[32] X. Sun, X. Ma, J. Wang et al., "Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21/VEGF signal," Oncotarget, vol. 8, no. 22, pp. 36137-36148, 2017.

[33] H. Haga, I. K. Yan, D. Borelli et al., "Extracellular vesicles from bone marrow derived mesenchymal stem cells protect against murine hepatic ischemia-reperfusion injury," Liver Transplantation, vol. 23, no. 6, pp. 791-803, 2017.

[34] M. Chopp and Z. G. Zhang, "Emerging potential of exosomes and noncoding microRNAs for the treatment of neurological injury/diseases," Expert Opinion on Emerging Drugs, vol. 20, no. 4, pp. 523-526, 2015.

[35] Y. X. Wang and J. M. Idee, "A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging," Quantitative Imaging in Medicine and Surgery, vol. 7, no. 1, pp. 88-122, 2017.

[36] P. Keselman, E. Y. Yu, X. Y. Zhou et al., "Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging," Physics in Medicine and Biology, vol. 62, no. 9, pp. 3440-3453, 2017.

[37] Q. Liang, Y. X. Wang, J. S. Ding et al., "Intra-arterial delivery of superparamagnetic iron-oxide nanoshell and polyvinyl alcohol based chemoembolization system for the treatment of liver tumor," Discovery Medicine, vol. 23, no. 124, pp. 27-39, 2017.

[38] A. S. Arbab, C. Thiffault, B. Navia et al., "Tracking of In-111-labeled human umbilical tissue-derived cells (hUTC) in a rat model of cerebral ischemia using SPECT imaging," BMC Medical Imaging, vol. 12, p. 33, 2012.

[39] Y. Tang, C. Zhang, J. Wang et al., "MRI/SPECT/fluorescent tri-modal probe for evaluating the homing and therapeutic efficacy of transplanted mesenchymal stem cells in a rat ischemic stroke model," Advanced Functional Materials, vol. 25, no. 7, pp. 1024-1034, 2015.

[40] P. Basset, J. P. Bellocq, C. Wolf et al., "A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas," Nature, vol. 348, no. 6303, pp. 699-704, 1990.

[41] M. M. Daadi, Z. Li, A. Arac et al., "Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain," Molecular Therapy, vol. 17, no. 7, pp. 1282-1291, 2009.

[42] Y. K. Choi, E. Urnukhsaikhan, H. H. Yoon, Y. K. Seo, and J. K. Park, "Effect of human mesenchymal stem cell transplantation on cerebral ischemic volume-controlled photothrombotic mouse model," Biotechnology Journal, vol. 11, no. 11, pp. 1397-1404, 2016.

[43] A. U. Hicks, R. S. Lappalainen, S. Narkilahti et al., "Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery," The European Journal of Neuroscience, vol. 29, no. 3, pp. 562-574, 2009.

[44] V. Darsalia, T. Kallur, and Z. Kokaia, "Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum," The European Journal of Neuroscience, vol. 26, no. 3, pp. 605-614, 2007.

[45] M. M. Daadi, A. L. Maag, and G. K. Steinberg, "Adherent self-renewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model," PLoS One, vol. 3, no. 2, article e1644, 2008.

[46] Y. Cheng, J. Zhang, L. Deng et al., "Intravenously delivered neural stem cells migrate into ischemic brain, differentiate and improve functional recovery after transient ischemic stroke in adult rats," International Journal of Clinical and Experimental Pathology, vol. 8, no. 3, pp. 2928-2936, 2015.

[47] R. H. Andres, N. Horie, W. Slikker et al., "Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain," Brain, vol. 134, Part 6, pp. 1777-1789, 2011.

[48] N. Horie, M. P. Pereira, K. Niizuma et al., "Transplanted stem cell-secreted vascular endothelial growth factor effects post-stroke recovery, inflammation, and vascular repair," Stem Cells, vol. 29, no. 2, pp. 274-285, 2011.

[49] C. Lois and A. Alvarez-Buylla, "Long-distance neuronal migration in the adult mammalian brain," Science, vol. 264, no. 5162, pp. 1145-1148, 1994.

[50] S. H. Koh and H. H. Park, "Neurogenesis in stroke recovery," Translational Stroke Research, vol. 8, no. 1, pp. 3-13, 2017.

[51] A. O. Ihunwo, L. H. Tembo, and C. Dzamalala, "The dynamics of adult neurogenesis in human hippocampus," Neural Regeneration Research, vol. 11, no. 12, pp. 1869-1883, 2016.

[52] K. L. Spalding, O. Bergmann, K. Alkass et al., "Dynamics of hippocampal neurogenesis in adult humans," Cell, vol. 153, no. 6, pp. 1219-1227, 2013.

[53] R. L. Zhang, M. Chopp, C. Roberts et al., "Stroke increases neural stem cells and angiogenesis in the neurogenic niche of the adult mouse," PLoS One, vol. 9, no. 12, article e113972, 2014.

[54] L. Ling, S. Zhang, Z. Ji et al., "Therapeutic effects of lipoprostaglandin E1 on angiogenesis and neurogenesis after ischemic stroke in rats," The International Journal of Neuroscience, vol. 126, no. 5, pp. 469-477, 2016.

[55] M. Nakata, T. Nakagomi, M. Maeda, A. Nakano-Doi, Y. Momota, and T. Matsuyama, "Induction of perivascular neural stem cells and possible contribution to neurogenesis following transient brain ischemia/reperfusion injury," Translational Stroke Research, vol. 8, no. 2, pp. 131-143, 2017.

[56] S. Ryu, S. H. Lee, S. U. Kim, and B. W. Yoon, "Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain," Neural Regeneration Research, vol. 11, no. 2, pp. 298-304, 2016.

[57] J. Marti-Fabregas, M. Romaguera-Ros, U. Gomez-Pinedo et al., "Proliferation in the human ipsilateral subventricular zone after ischemic stroke," Neurology, vol. 74, no. 5, pp. 357-365, 2010.

[58] C. A. Gregoire, B. L. Goldenstein, E. M. Floriddia, F. Barnabe-Heider, and K. J. Fernandes, "Endogenous neural stem cell responses to stroke and spinal cord injury," Glia, vol. 63, no. 8, pp. 1469-1482, 2015.

[59] T. Hayashi, N. Noshita, T. Sugawara, and P. H. Chan, "Temporal profile of angiogenesis and expression of related genes in the brain after ischemia," Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 2, pp. 166-180, 2003.

[60] M. Faiz, N. Sachewsky, S. Gascon, K. W. Bang, C. M. Morshead, and A. Nagy, "Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke," Cell Stem Cell, vol. 17, no. 5, pp. 624-634, 2015.

[61] I. A. Qureshi and M. F. Mehler, "Chromatin-modifying agents for epigenetic reprogramming and endogenous neural stem cell-mediated repair in stroke," Translational Stroke Research, vol. 2, no. 1, pp. 7-16, 2011.

[62] M. Song, S. P. Yu, O. Mohamad et al., "Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice," Neurobiology of Disease, vol. 98, pp. 9-24, 2017.

[63] G. Camussi, M. C. Deregibus, and V. Cantaluppi, "Role of stem-cell-derived microvesicles in the paracrine action of stem cells," Biochemical Society Transactions, vol. 41, no. 1, pp. 283-287, 2013.

[64] T. R. Doeppner, J. Herz, A. Gorgens et al., "Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression," Stem Cells Translational Medicine, vol. 4, no. 10, pp. 1131-1143, 2015.

[65] B. Gyorgy, M. E. Hung, X. O. Breakefield, and J. N. Leonard, "Therapeutic applications of extracellular vesicles: clinical promise and open questions," Annual Review of Pharmacology and Toxicology, vol. 55, pp. 439-464, 2015.

[66] B. Zheng, W. N. Yin, T. Suzuki et al., "Exosome-mediated miR-155 transfer from smooth muscle cells to endothelial cells induces endothelial injury and promotes atherosclerosis," Molecular Therapy, vol. 25, no. 6, pp. 1279-1294, 2017.

[67] L. Qu, J. Ding, C. Chen et al., "Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA," Cancer Cell, vol. 29, no. 5, pp. 653-668, 2016.

[68] G. K. Panigrahi and G. Deep, "Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer," Frontiers in Bioscience (Landmark Edition), vol. 22, pp. 1682-1696, 2017.

[69] R. Xu, D. W. Greening, H. J. Zhu, N. Takahashi, and R. J. Simpson, "Extracellular vesicle isolation and characterization: toward clinical application," The Journal of Clinical Investigation, vol. 126, no. 4, pp. 1152-1162, 2016.

[70] V. Hyenne, M. Labouesse, and J. G. Goetz, "The small GTPase Ral orchestrates MVB biogenesis and exosome secretion," Small GTPases, pp. 1-7, 2016.

[71] J. Kowal, M. Tkach, and C. Thery, "Biogenesis and secretion of exosomes," Current Opinion in Cell Biology, vol. 29, pp. 116-125, 2014.

[72] H. Xin, Y. Li, Y. Cui, J. J. Yang, Z. G. Zhang, and M. Chopp, "Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats," Journal of Cerebral Blood Flow and Metabolism, vol. 33, no. 11, pp. 1711-1715, 2013.

[73] H. Xin, F. Wang, Y. Li et al., "Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b overexpressing multipotent mesenchymal stromal cells," Cell Transplantation, vol. 26, no. 2, pp. 243-257, 2017.

[74] K. H. Chen, C. H. Chen, C. G. Wallace et al., "Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke," Oncotarget, vol. 7, no. 46, pp. 74537-74556, 2016.

[75] W. T. Tse, J. D. Pendleton, W. M. Beyer, M. C. Egalka, and E. C. Guinan, "Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation," Transplantation, vol. 75, no. 3, pp. 389-397, 2003.

[76] D. J. Chang, N. Lee, C. Choi et al., "Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion," Cell Transplantation, vol. 22, no. 8, pp. 1441-1452, 2013.

[77] S. Rosenblum, T. N. Smith, N. Wang et al., "BDNF pretreatment of human embryonic-derived neural stem cells improves cell survival and functional recovery after transplantation in hypoxic-ischemic stroke," Cell Transplantation, vol. 24, no. 12, pp. 2449-2461, 2015.

[78] E. Atangana, U. C. Schneider, K. Blecharz et al., "Intravascular inflammation triggers intracerebral activated microglia and contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH)," Translational Stroke Research, vol. 8, no. 2, pp. 144-156, 2017.

[79] N. Sun, R. F. Keep, Y. Hua, and G. Xi, "Critical role of the sphingolipid pathway in stroke: a review of current utility and potential therapeutic targets," Translational Stroke Research, vol. 7, no. 5, pp. 420-438, 2016.

[80] C. Justicia, J. Panes, S. Sole et al., "Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats," Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 12, pp. 1430-1440, 2003.

[81] E. Kolaczkowska and P. Kubes, "Neutrophil recruitment and function in health and inflammation," Nature Reviews Immunology, vol. 13, no. 3, pp. 159-175, 2013.

[82] A. Cervera, A. M. Planas, C. Justicia et al., "Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke," PLoS One, vol. 5, no. 2, article e8433, 2010.

[83] B. Lv, F. Li, J. Han et al., "Hif-1alpha overexpression improves transplanted bone mesenchymal stem cells survival in rat MCAO stroke model," Frontiers in Molecular Neuroscience, vol. 10, p. 80, 2017.

[84] A. Aziz, E. Soucie, S. Sarrazin, and M. H. Sieweke, "MafB/ c-Maf deficiency enables self-renewal of differentiated functional macrophages," Science, vol. 326, no. 5954, pp. 867-871, 2009.

[85] E. L. Soucie, Z. Weng, L. Geirsdottir et al., "Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells," Science, vol. 351, no. 6274, article aad5510, 2016.

[86] T. Shichita, M. Ito, R. Morita et al., "MAFB prevents excess inflammation after ischemic stroke by accelerating clearance of damage signals through MSR1," Nature Medicine, vol. 23, no. 6, pp. 723-732, 2017.

[87] R. S. Pandya, L. Mao, H. Zhou et al., "Central nervous system agents for ischemic stroke: neuroprotection mechanisms," Central Nervous System Agents in Medicinal Chemistry, vol. 11, no. 2, pp. 81-97, 2011.

[88] N. A. Belle, G. D. Dalmolin, G. Fonini, M. A. Rubin, and J. B. Rocha, "Polyamines reduces lipid peroxidation induced by different pro-oxidant agents," Brain Research, vol. 1008, no. 2, pp. 245-251, 2004.

[89] J. Li, K. M. Doyle, and T. Tatlisumak, "Polyamines in the brain: distribution, biological interactions, and their potential therapeutic role in brain ischaemia," Current Medicinal Chemistry, vol. 14, no. 17, pp. 1807-1813, 2007.

[90] M. D. Shirhan, S. M. Moochhala, P. Y. Ng et al., "Spermine reduces infarction and neurological deficit following a rat model of middle cerebral artery occlusion: a magnetic resonance imaging study," Neuroscience, vol. 124, no. 2, pp. 299-304, 2004.

[91] T. H. Shin, G. Phukan, J. S. Shim et al., "Restoration of polyamine metabolic patterns in in vivo and in vitro model of ischemic stroke following human mesenchymal stem cell treatment," Stem Cells International, vol. 2016, Article ID 4612531, 11 pages, 2016.

[92] N. Egawa, J. Lok, K. Washida, and K. Arai, "Mechanisms of axonal damage and repair after central nervous system injury," Translational Stroke Research, vol. 8, no. 1, pp. 14-21,2017.

[93] C. Xing, K. Hayakawa, and E. H. Lo, "Mechanisms, imaging, and therapy in stroke recovery," Translational Stroke Research, vol. 8, no. 1, pp. 1-2, 2017.

[94] H. Xin, Y. Li, Z. Liu et al., "MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles," Stem Cells, vol. 31, no. 12, pp. 2737-2746, 2013.

[95] H. Xin, Y. Li, B. Buller et al., "Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth," Stem Cells, vol. 30, no. 7, pp. 1556-1564, 2012.

[96] G. K. Steinberg, D. Kondziolka, L. R. Wechsler et al., "Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study," Stroke, vol. 47, no. 7, pp. 1817-1824, 2016.

[97] Q. Vu, K. Xie, M. Eckert, W. Zhao, and S. C. Cramer, "Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke," Neurology, vol. 82, no. 14, pp. 12771286, 2014.

[98] D. Kondziolka, G. K. Steinberg, L. Wechsler et al., "Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial," Journal of Neurosurgery, vol. 103, no. 1, pp. 38-45, 2005.

[99] K. Prasad, A. Sharma, A. Garg et al., "Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial," Stroke, vol. 45, no. 12, pp. 3618-3624, 2014.

[100] A. A. Ghali, M. K. Yousef, O. A. Ragab, and E. A. ElZamarany, "Intra-arterial infusion of autologous bone marrow mononuclear stem cells in subacute ischemic stroke patients," Frontiers in Neurology, vol. 7, p. 228, 2016.

[101] M. G. Liska, M. G. Crowley, and C. V. Borlongan, "Regulated and unregulated clinical trials of stem cell therapies for stroke," Translational Stroke Research, vol. 8, no. 2, pp. 93-103, 2017.

[102] V. F. Segers and R. T. Lee, "Stem-cell therapy for cardiac disease," Nature, vol. 451, no. 7181, pp. 937-942, 2008.

[103] B. Rodriguez-Frutos, L. Otero-Ortega, M. Gutierrez-Fernandez, B. Fuentes, J. Ramos-Cejudo, and E. DiezTejedor, "Stem cell therapy and administration routes after stroke," Translational Stroke Research, vol. 7, no. 5, pp. 378-387, 2016.

[104] J. Biernaskie, D. Corbett, J. Peeling, J. Wells, and H. Lei, "A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats," Magnetic Resonance in Medicine, vol. 46, no. 4, pp. 827-830, 2001.

[105] Z. Z. Wei, X. Gu, A. Ferdinand et al., "Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats," Cell Transplantation, vol. 24, no. 3, pp. 391-402, 2015.

[106] N. Wei, S. P. Yu, X. Gu et al., "Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice," Cell Transplantation, vol. 22, no. 6, pp. 977-991, 2013.

[107] M. Srinivas, P. Boehm-Sturm, C. G. Figdor, I. J. de Vries, and M. Hoehn, "Labeling cells for in vivo tracking using (19)F MRI," Biomaterials, vol. 33, no. 34, pp. 8830-8840, 2012.

[108] T. J. Wu, Y. K. Tzeng, W. W. Chang et al., "Tracking the engraftment and regenerative capabilities of transplanted lung stem cells using fluorescent nanodiamonds," Nature Nanotechnology, vol. 8, no. 9, pp. 682-689, 2013.

[109] X. Liang, L. Fang, X. Li, X. Zhang, and F. Wang, "Activatable near infrared dye conjugated hyaluronic acid based nanoparticles as a targeted theranostic agent for enhanced fluorescence/CT/photoacoustic imaging guided photothermal therapy," Biomaterials, vol. 132, pp. 72-84, 2017.

[110] A. B. Alenazy, R. G. Wells, and T. D. Ruddy, "New solid state cadmium-zinc-telluride technology for cardiac single photon emission computed tomographic myocardial perfusion imaging," Expert Review of Medical Devices, vol. 14, no. 3, pp. 213-222, 2017.

[111] A. T. Chan and M. R. Abraham, "SPECT and PET to optimize cardiac stem cell therapy," Journal of Nuclear Cardiology, vol. 19, no. 1, pp. 118-125, 2012.

[112] O. Detante, S. Valable, F. de Fraipont et al., "Magnetic resonance imaging and fluorescence labeling of clinical-grade mesenchymal stem cells without impacting their phenotype: study in a rat model of stroke," Stem Cells Translational Medicine, vol. 1, no. 4, pp. 333-341, 2012.

[113] P. Hua, Y. Y. Wang, L. B. Liu et al., "In vivo magnetic resonance imaging tracking of transplanted superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells in rats with myocardial infarction," Molecular Medicine Reports, vol. 11, no. 1, pp. 113-120, 2015.

[114] L. Li, Q. Jiang, G. Ding et al., "Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study," Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 3, pp. 653-662, 2010.

[115] J. H. Cho, K. S. Hong, J. Cho et al., "Detection of iron-labeled single cells by MR imaging based on intermolecular double quantum coherences at 14 T," Journal of Magnetic Resonance, vol. 217, pp. 86-91, 2012.

[116] T. J. England, P. M. Bath, M. Abaei, D. Auer, and D. R. Jones, "Hematopoietic stem cell (CD34+) uptake of superparamagnetic iron oxide is enhanced by but not dependent on a transfection agent," Cytotherapy, vol. 15, no. 3, pp. 384-390, 2013.

[117] L. Zhang, Y. Wang, Y. Tang et al., "High MRI performance fluorescent mesoporous silica-coated magnetic nanoparticles for tracking neural progenitor cells in an ischemic mouse model," Nanoscale, vol. 5, no. 10, pp. 4506-4516, 2013.

[118] Y. Wang, F. Xu, C. Zhang et al., "High MR sensitive fluorescent magnetite nanocluster for stem cell tracking in ischemic mouse brain," Nanomedicine, vol. 7, no. 6, pp. 1009-1019, 2011.

[119] S. S. Lu, S. Liu, Q. Q. Zuet al., "In vivo MR imaging of intraarterially delivered magnetically labeled mesenchymal stem cells in a canine stroke model," PLoS One, vol. 8, no. 2, article e54963, 2013.

[120] M. A. Kolecka, S. Arnhold, M. Schmidt et al., "Behaviour of adipose-derived canine mesenchymal stem cells after superparamagnetic iron oxide nanoparticles labelling for magnetic resonance imaging," BMC Veterinary Research, vol. 13, no. 1, p. 62, 2017.

[121] H. Ittrich, K. Peldschus, N. Raabe, M. Kaul, and G. Adam, "Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy," Rofo, vol. 185, no. 12, pp. 1149-1166, 2013.

[122] E. U. Saritas, P. W. Goodwill, L. R. Croft et al., "Magnetic particle imaging (MPI) for NMR and MRI researchers," Journal of Magnetic Resonance, vol. 229, pp. 116-126, 2013.

[123] J. Weizenecker, B. Gleich, J. Rahmer, H. Dahnke, and J. Borgert, "Three-dimensional real-time in vivo magnetic particle imaging," Physics in Medicine and Biology, vol. 54, no. 5, pp. L1-L10, 2009.

[124] P. W. Goodwill and S. M. Conolly, "The X-space formulation of the magnetic particle imaging process: 1-D signal, resolution, bandwidth, SNR, SAR, and magnetostimulation," IEEE Transactions on Medical Imaging, vol. 29, no. 11, pp. 1851-1859, 2010.

[125] X. Y. Zhou, K. E. Jeffris, E. Y. Yu et al., "First in vivo magnetic particle imaging of lung perfusion in rats," Physics in Medicine and Biology, vol. 62, no. 9, pp. 3510-3522, 2017.

[126] B. Zheng, E. Yu, R. Orendorff et al., "Seeing SPIOs directly in vivo with magnetic particle imaging," Molecular Imaging and Biology, vol. 19, no. 3, pp. 385-390, 2017.

[127] A. P. Khandhar, P. Keselman, S. J. Kemp et al., "Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging," Nanoscale, vol. 9, no. 3, pp. 1299-1306, 2017.

[128] B. Zheng, M. P. von See, E. Yu et al., "Quantitative magnetic particle imaging monitors the transplantation, biodistribution, and clearance of stem cells in vivo," Theranostics, vol. 6, no. 3, pp. 291-301, 2016.

[129] B. Zheng, T. Vazin, P. W. Goodwill et al., "Magnetic particle imaging tracks the long-term fate of in vivo neural cell implants with high image contrast," Scientific Reports, vol. 5, p. 14055, 2015.

[130] Z. Cai, N. Chattopadhyay, K. Yang et al., "111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection," Nuclear Medicine and Biology, vol. 43, no. 12, pp. 818-826, 2016.

[131] B. Nowak, C. Weber, A. Schober et al., "Indium-111 oxine labelling affects the cellular integrity of haematopoietic progenitor cells," European Journal of Nuclear Medicine and Molecular Imaging, vol. 34, no. 5, pp. 715-721, 2007.

[132] Y. Wang, C. Xu, and H. Ow, "Commercial nanoparticles for stem cell labeling and tracking," Theranostics, vol. 3, no. 8, pp. 544-560, 2013.

[133] J. Ding, Z. Zhao, C. Wang et al., "Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model," Brain Research, vol. 1642, pp. 209-218, 2016.

[134] C. Vandeputte, V. Reumers, S. A. Aelvoet et al., "Bioluminescence imaging of stroke-induced endogenous neural stem cell response," Neurobiology of Disease, vol. 69, pp. 144-155, 2014.

[135] P. J. Chen, Y. D. Kang, C. H. Lin et al., "Multitheragnostic multi-GNRs crystal-seeded magnetic nanoseaurchin for enhanced in vivo mesenchymal-stem-cell homing, multimodal imaging, and stroke therapy," Advanced Materials, vol. 27, no. 41, pp. 6488-6495, 2015.

[136] D. Granot and E. M. Shapiro, "Accumulation of micron sized iron oxide particles in endothelin-1 induced focal cortical ischemia in rats is independent of cell migration," Magnetic Resonance in Medicine, vol. 71, no. 4, pp. 1568-1574, 2014.

[137] K. Li, M. Yamamoto, S. J. Chan et al., "Organic nanoparticles with aggregation-induced emission for tracking bone marrow stromal cells in the rat ischemic stroke model," Chemical Communications (Camb), vol. 50, no. 96, pp. 15136-15139, 2014.

[138] E. S. Lee, J. Chan, B. Shuter et al., "Microgel iron oxide nanoparticles for tracking human fetal mesenchymal stem cells through magnetic resonance imaging," Stem Cells, vol. 27, no. 8, pp. 1921-1931, 2009.

[139] W. C. Shyu, C. P. Chen, S. Z. Lin, Y. J. Lee, and H. Li, "Efficient tracking of non-iron-labeled mesenchymal stem cells with serial MRI in chronic stroke rats," Stroke, vol. 38, no. 2, pp. 367-374, 2007.

[140] K. S. Jang, K. S. Lee, S. H. Yang, and S. S. Jeun, "In vivo tracking of transplanted bone marrow-derived mesenchymal stem cells in a murine model of stroke by bioluminescence imaging," Journal of Korean Neurosurgical Association, vol. 48, no. 5, pp. 391-398, 2010.

Yanhong Zhang (1) and Honghong Yao (1, 2)

(1) Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China

(2) Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu 210096, China

Correspondence should be addressed to Honghong Yao; yaohh@seu.edu.cn

Received 6 May 2017; Revised 8 July 2017; Accepted 30 July 2017; Published 20 August 2017

Academic Editor: Yao Li
TABLE 1: Tracer agents currently available for tracking stem cells
in stroke.

Tracer agent                 Imaging     Labeled       Route of
                            modality    cell type   administration

Radiotracer

  [sup.111]In oxine           SPECT       hUTC            IV

Nanoparticles

  SPIOs                     3.0T MRI      MSCs            IA

                            4.7T MRI      NSCs            IC

                            MRI, BLI      hNSCs           IC

  MPIOs                        MRI       eNSCs/           IC
                                          NPCs

                               MRI        hMSCs           IC

  FMNC                         MRI        MSCs            IC

  fmSI[O.sub.4]@SPIONs      3.0T MRI      NPCs          IC/IA

  AIE NPs                      FLI        BMSCs           IC

  GRMNBs                    PA, 7.0T      MSCs            IV
                            MRI, IVIS

  MGIO                      1.5T MRI     hfMSCs           IV

  Gd-DTPA                      MRI        BMSCs           IC

Report gene

  D-luciferin                  BLI        BMSC            IP

  Fluc and eGFP condition   BLI, MRI      eNSCs           IC
  lentiviral vectors
  (Cre-Flex-LVs)

  GFP and Luc2 double          BLI        ECFC            IA
  fusion reporter gene

Tracer agent                 Imaging               Results
                            modality

Radiotracer

  [sup.111]In oxine           SPECT          Approximately 1% of
                                        transplanted cells migrate to
                                             the site of injury,
                                           increasing vascular and
                                        synaptic densities in the IBZ
                                                    [38]

Nanoparticles

  SPIOs                     3.0T MRI         Safe and feasible;
                                         ipsilateral MCA conditions
                                            and infarction volume
                                        affected the number of cells
                                                grafted [119]

                            4.7T MRI           The majority of
                                        contralaterally grafted NSCs
                                        migrated to the peri-infarct
                                                  area [76]

                            MRI, BLI        Tracking the fate and
                                         function of implanted cells
                                          in real time for 2 months
                                                    [41]

  MPIOs                        MRI       Immediate, cell-independent
                                        MPIO accumulation at the site
                                               of injury [136]

                               MRI      Good label stability, did not
                                         affect hMSC viability [112]

  FMNC                         MRI      Safe and high efficiency for
                                        cell labeling, migration, and
                                        accumulation in the ischemic
                                                region [118]

  fmSI[O.sub.4]@SPIONs      3.0T MRI    High MR sensitivity and cell
                                          labeling efficiency [117]

  AIE NPs                      FLI      Low cytotoxicity and feasible
                                                    [137]

  GRMNBs                    PA, 7.0T    Enhanced stem cell homing and
                            MRI, IVIS      reduced infarct volume,
                                        allowed short- and long-term
                                              monitoring [135]

  MGIO                      1.5T MRI      Low toxicity and feasible
                                                    [138]

  Gd-DTPA                      MRI        Safe and high efficiency
                                                    [139]

Report gene

  D-luciferin                  BLI       Higher signal intensity of
                                        luciferase-expressing BMSCs 2
                                         h after transplantation and
                                         migration to the IBZ [140]

  Fluc and eGFP condition   BLI, MRI      A significant increase in
  lentiviral vectors                       eNSC proliferation and
  (Cre-Flex-LVs)                         migration, and 21% of cells
                                             differentiated into
                                        astrocytes and neurons [134]

  GFP and Luc2 double          BLI      Functional recovery, improved
  fusion reporter gene                   angiogenesis, neurogenesis,
                                        and increased apoptosis [133]

SPECT: single photon emission computed tomography; hUTC: human
umbilical tissue-derived cells; IV: intravenous; IBZ: the ischemic
boundary zone; SPIOs: superparamagnetic iron oxide; MRI: magnetic
resonance imaging; MSCs: mesenchymal stem cells; IA:
intra-arterial; MCA: middle cerebral artery; NSCs: endogenous
neural stem cells; IC: intracerebral; BLI: bioluminescence imaging;
hMSCs: human MSCs; MPIO: micron-sized superparamagnetic iron oxide;
eNSCs: endogenous NSCs; NPS: neural progenitor cell; FMNC:
fluorescent magnetite nano cluster; fmSIO4@SPIONs: fluorescent
mesoporous silicacoated superparamagnetic iron oxide nanoparticles;
AIE NPs: fluorescent nanoparticles with aggregation-induced
emission; FLI: fluorescent imaging; BMSCs: bone marrow-derived
MSCs; GRMNBs: multigold nanorod (multiGNR) crystal-seeded magnetic
mesoporous silica nanobeads; PAI: photoacoustic imaging; IVIS:
interactive video information system; MGIO: microgel iron oxide;
hfMSCs: human fetal MSCs; IP: intraperitoneal; Fluc: firefly
luciferase; eGFP: enhanced green fluorescent protein; eNSCs:
endogenous NSCs; ECFC: endothelial colony-forming cell.
COPYRIGHT 2017 COPYRIGHT 2010 SAGE-Hindawi Access to Research
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Zhang, Yanhong; Yao, Honghong
Publication:Stem Cells International
Article Type:Report
Date:Jan 1, 2017
Words:9647
Previous Article:Immunoprofiling of Adult-Derived Human Liver Stem/Progenitor Cells: Impact of Hepatogenic Differentiation and Inflammation.
Next Article:Signal Factors Secreted by 2D and Spheroid Mesenchymal Stem Cells and by Cocultures of Mesenchymal Stem Cells Derived Microvesicles and Retinal...
Topics:

Terms of use | Privacy policy | Copyright © 2020 Farlex, Inc. | Feedback | For webmasters