Publications by authors named "Samantha Spellicy"

9 Publications

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The Immunomodulatory Capacity of Induced Pluripotent Stem Cells in the Post-stroke Environment.

Front Cell Dev Biol 2021 16;9:647415. Epub 2021 Mar 16.

Dean's Office, Medical College of Georgia at Augusta University, Augusta, GA, United States.

Inflammation has proven to be a key contributing factor to the pathogenesis of ischemic and hemorrhagic stroke. This sequential and progressive response, marked by proliferation of resident immune cells and recruitment of peripheral immune populations, results in increased oxidative stress, and neuronal cell death. Therapeutics aimed at quelling various stages of this post-stroke inflammatory response have shown promise recently, one of which being differentiated induced pluripotent stem cells (iPSCs). While direct repopulation of damaged tissues and enhanced neurogenesis are hypothesized to encompass some of the therapeutic potential of iPSCs, recent evidence has demonstrated a substantial paracrine effect on neuroinflammation. Specifically, investigation of iPSCs, iPSC-neural progenitor cells (iPSC-NPCs), and iPSC-neuroepithelial like stem cells (iPSC-lt-NESC) has demonstrated significant immunomodulation of proinflammatory signaling and endogenous inflammatory cell populations, such as microglia. This review aims to examine the mechanisms by which iPSCs mediate neuroinflammation in the post-stroke environment, as well as delineate avenues for further investigation.
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http://dx.doi.org/10.3389/fcell.2021.647415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007866PMC
March 2021

Exploring the predictive value of lesion topology on motor function outcomes in a porcine ischemic stroke model.

Sci Rep 2021 Feb 15;11(1):3814. Epub 2021 Feb 15.

Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.

Harnessing the maximum diagnostic potential of magnetic resonance imaging (MRI) by including stroke lesion location in relation to specific structures that are associated with particular functions will likely increase the potential to predict functional deficit type, severity, and recovery in stroke patients. This exploratory study aims to identify key structures lesioned by a middle cerebral artery occlusion (MCAO) that impact stroke recovery and to strengthen the predictive capacity of neuroimaging techniques that characterize stroke outcomes in a translational porcine model. Clinically relevant MRI measures showed significant lesion volumes, midline shifts, and decreased white matter integrity post-MCAO. Using a pig brain atlas, damaged brain structures included the insular cortex, somatosensory cortices, temporal gyri, claustrum, and visual cortices, among others. MCAO resulted in severely impaired spatiotemporal gait parameters, decreased voluntary movement in open field testing, and higher modified Rankin Scale scores at acute timepoints. Pearson correlation analyses at acute timepoints between standard MRI metrics (e.g., lesion volume) and functional outcomes displayed moderate R values to functional gait outcomes. Moreover, Pearson correlation analyses showed higher R values between functional gait deficits and increased lesioning of structures associated with motor function, such as the putamen, globus pallidus, and primary somatosensory cortex. This correlation analysis approach helped identify neuroanatomical structures predictive of stroke outcomes and may lead to the translation of this topological analysis approach from preclinical stroke assessment to a clinical biomarker.
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http://dx.doi.org/10.1038/s41598-021-83432-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884696PMC
February 2021

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models.

Front Neurol 2020 21;11:594954. Epub 2021 Jan 21.

Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.

The Stroke Therapy Academic Industry Roundtable (STAIR) has recommended that novel therapeutics be tested in a large animal model with similar anatomy and physiology to humans. The pig is an attractive model due to similarities in brain size, organization, and composition relative to humans. However, multiple pig breeds have been used to study ischemic stroke with potentially differing cerebral anatomy, architecture and, consequently, ischemic stroke pathologies. The objective of this study was to characterize brain anatomy and assess spatiotemporal gait parameters in Yucatan (YC) and Landrace (LR) pigs pre- and post-stroke using magnetic resonance imaging (MRI) and gait analysis, respectively. Ischemic stroke was induced via permanent middle cerebral artery occlusion (MCAO). MRI was performed pre-stroke and 1-day post-stroke. Structural and diffusion-tensor sequences were performed at both timepoints and analyzed for cerebral characteristics, lesion diffusivity, and white matter changes. Spatiotemporal and relative pressure gait measurements were collected pre- and 2-days post-stroke to characterize and compare acute functional deficits. The results from this study demonstrated that YC and LR pigs exhibit differences in gross brain anatomy and gait patterns pre-stroke with MRI and gait analysis showing statistical differences in the majority of parameters. However, stroke pathologies in YC and LR pigs were highly comparable post-stroke for most evaluated MRI parameters, including lesion volume and diffusivity, hemisphere swelling, ventricle compression, caudal transtentorial and foramen magnum herniation, showing no statistical difference between the breeds. In addition, post-stroke changes in velocity, cycle time, swing percent, cadence, and mean hoof pressure showed no statistical difference between the breeds. These results indicate significant differences between pig breeds in brain size, anatomy, and motor function pre-stroke, yet both demonstrate comparable brain pathophysiology and motor outcomes post-stroke. The conclusions of this study suggest pigs of these different breeds generally show a similar ischemic stroke response and findings can be compared across porcine stroke studies that use different breeds.
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http://dx.doi.org/10.3389/fneur.2020.594954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859633PMC
January 2021

Semi-Automated Cell and Tissue Analyses Reveal Regionally Specific Morphological Alterations of Immune and Neural Cells in a Porcine Middle Cerebral Artery Occlusion Model of Stroke.

Front Cell Neurosci 2020 22;14:600441. Epub 2021 Jan 22.

Regenerative Bioscience Center, University of Georgia, Athens, GA, United States.

Histopathological analysis of cellular changes in the stroked brain provides critical information pertaining to inflammation, cell death, glial scarring, and other dynamic injury and recovery responses. However, commonly used manual approaches are hindered by limitations in speed, accuracy, bias, and the breadth of morphological information that can be obtained. Here, a semi-automated high-content imaging (HCI) and CellProfiler histological analysis method was developed and used in a Yucatan miniature pig permanent middle cerebral artery occlusion (pMCAO) model of ischemic stroke to overcome these limitations. Evaluation of 19 morphological parameters in IBA1 microglia/macrophages, GFAP astrocytes, NeuN neuronal, FactorVIII vascular endothelial, and DCX neuroblast cell areas was conducted on porcine brain tissue 4 weeks post pMCAO. Out of 19 morphological parameters assessed in the stroke perilesional and ipsilateral hemisphere regions (38 parameters), a significant change in measured IBA1 parameters, GFAP parameters, NeuN parameters, FactorVIII parameters, and DCX parameters were observed in stroked vs. non-stroked animals. Principal component analysis (PCA) and correlation analyses demonstrated that stroke-induced significant and predictable morphological changes that demonstrated strong relationships between IBA1, GFAP, and NeuN areas. Ultimately, this unbiased, semi-automated HCI and CellProfiler histopathological analysis approach revealed regional and cell specific morphological signatures of immune and neural cells after stroke in a highly translational porcine model. These identified features can provide information of disease pathogenesis and evolution with high resolution, as well as be used in therapeutic screening applications.
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http://dx.doi.org/10.3389/fncel.2020.600441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862775PMC
January 2021

Tissue and Stem Cell Sourced Extracellular Vesicle Communications with Microglia.

Stem Cell Rev Rep 2021 Apr;17(2):357-368

Regenerative Bioscience Center, Department of Animal and Dairy Science, Rhodes Center for Animal and Dairy Science, University of Georgia, 425 River Road, Athens, GA, 30602, USA.

Extracellular vesicles (EVs), nano- to micro- sized vesicles released from cells, have garnered attention in recent years for their role in intercellular communication. Specifically, EVs from various cell sources including stem cells, have shown to have an exacerbatory or therapeutic effect in the content of pro- and anti-inflammatory environments through their interaction with immune recipient cells. This review aims to the coalescence information surrounding EVs derived from various sources and their interaction with microglia in neutral, anti, and pro- inflammatory environments. Overall, in homeostatic environments, EVs from many CNS lineages have been shown to have specific interactions with recipient microglia. In complex inflammatory environments, such as the tumor micro-environment (TME), EVs have been shown to further influence immune dampening through transition of microglia to a more M2-like phenotype. While not advantageous in the TME, this effect can be harnessed therapeutically in proinflammatory neurological conditions such as stroke, Alzheimer's, and Parkinson's. EVs derived from various stem cell and non-stem cell derived sources were found to attenuate proinflammatory responses in microglia in in vitro and in vivo models of these conditions. EVs loaded with anti-inflammatory therapeutics furthered this anti-inflammatory effect on recipient microglia. Graphical Abstract Extracellular Vesicles (EVs) from multiple cells types modulate microglial polarization. Cartoon depicting common ways microglia are activated through inflammatory and disease processes. EVs, derived from stem and non-stem sources, have been shown to attenuate proinflammatory responses in in vitro and in vivo.
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http://dx.doi.org/10.1007/s12015-020-10011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036211PMC
April 2021

Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model.

Transl Stroke Res 2020 08 6;11(4):776-788. Epub 2019 Dec 6.

Regenerative Bioscience Center, University of Georgia, Athens, GA, 30602, USA.

Magnetic resonance imaging (MRI) is a clinically relevant non-invasive imaging tool commonly utilized to assess stroke progression in real time. This study investigated the utility of MRI as a predictive measure of clinical and functional outcomes when a stroke intervention is withheld or provided, in order to identify biomarkers for stroke functional outcome under these conditions. Fifteen MRI and ninety functional parameters were measured in a middle cerebral artery occlusion (MCAO) porcine ischemic stroke model. Multiparametric analysis of correlations between MRI measurements and functional outcome was conducted. Acute axial and coronal midline shift (MLS) at 24 h post-stroke were associated with decreased survival and recovery measured by modified Rankin scale (mRS) and were significantly correlated with 52 measured acute (day 1 post) and chronic (day 84 post) gait and behavior impairments in non-treated stroked animals. These results suggest that MLS may be an important non-invasive biomarker that can be used to predict patient outcomes and prognosis as well as guide therapeutic intervention and rehabilitation in non-treated animals and potentially human patients that do not receive interventional treatments. Neural stem cell-derived extracellular vesicle (NSC EV) was a disruptive therapy because NSC EV administration post-stroke disrupted MLS correlations observed in non-treated stroked animals. MLS was not associated with survival and functional outcomes in NSC EV-treated animals. In contrast to untreated animals, NSC EVs improved stroked animal outcomes regardless of MLS severity.
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http://dx.doi.org/10.1007/s12975-019-00753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340639PMC
August 2020

Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury.

J Neurotrauma 2020 06 10;37(11):1358-1369. Epub 2020 Feb 10.

Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.

The lack of effective therapies for moderate-to-severe traumatic brain injuries (TBIs) leaves patients with lifelong disabilities. Neural stem cells (NSCs) have demonstrated great promise for neural repair and regeneration. However, direct evidence to support their use as a cell replacement therapy for neural injuries is currently lacking. We hypothesized that NSC-derived extracellular vesicles (NSC EVs) mediate repair indirectly after TBI by enhancing neuroprotection and therapeutic efficacy of endogenous NSCs. We evaluated the short-term effects of acute intravenous injections of NSC EVs immediately following a rat TBI. Male NSC EV-treated rats demonstrated significantly reduced lesion sizes, enhanced presence of endogenous NSCs, and attenuated motor function impairments 4 weeks post-TBI, when compared with vehicle- and TBI-only male controls. Although statistically not significant, we observed a therapeutic effect of NSC EVs on brain lesion volume, nestin expression, and behavioral recovery in female subjects. Our study demonstrates the neuroprotective and functional benefits of NSC EVs for treating TBI and points to gender-dependent effects on treatment outcomes, which requires further investigation.
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http://dx.doi.org/10.1089/neu.2019.6443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249471PMC
June 2020

Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke.

Stroke 2018 05 12;49(5):1248-1256. Epub 2018 Apr 12.

Regenerative Bioscience Center (R.L.W., E.E.K., B.J.J., S.S., F.D.W., S.L. Stice)

Background And Purpose: Recent work from our group suggests that human neural stem cell-derived extracellular vesicle (NSC EV) treatment improves both tissue and sensorimotor function in a preclinical thromboembolic mouse model of stroke. In this study, NSC EVs were evaluated in a pig ischemic stroke model, where clinically relevant end points were used to assess recovery in a more translational large animal model.

Methods: Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO), and either NSC EV or PBS treatment was administered intravenously at 2, 14, and 24 hours post-MCAO. NSC EV effects on tissue level recovery were evaluated via magnetic resonance imaging at 1 and 84 days post-MCAO. Effects on functional recovery were also assessed through longitudinal behavior and gait analysis testing.

Results: NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs (0 of 7) versus control pigs (7 of 8). NSC EV-treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs 1-day post-MCAO. NSC EVs significantly reduced edema in treated pigs relative to control pigs, as assessed by improved diffusivity through apparent diffusion coefficient maps. NSC EVs preserved white matter integrity with increased corpus callosum fractional anisotropy values 84 days post-MCAO. Behavior and mobility improvements paralleled structural changes as NSC EV-treated pigs exhibited improved outcomes, including increased exploratory behavior and faster restoration of spatiotemporal gait parameters.

Conclusions: This study demonstrated for the first time that in a large animal model novel NSC EVs significantly improved neural tissue preservation and functional levels post-MCAO, suggesting NSC EVs may be a paradigm changing stroke therapeutic.
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http://dx.doi.org/10.1161/STROKEAHA.117.020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916046PMC
May 2018

Minocycline in Acute Cerebral Hemorrhage: An Early Phase Randomized Trial.

Stroke 2017 10 8;48(10):2885-2887. Epub 2017 Sep 8.

From the Department of Neurology, Medical College of Georgia, Augusta (S.S., J.L.W., W.Z., D.C.H., A.E., J.A.S.); University of Georgia College of Pharmacy, Athens (A.Y.F., A.S.N., S.C.F.); and University of Waterloo, Ontario, Canada (D.J.E.).

Background And Purpose: Minocycline is under investigation as a neurovascular protective agent for stroke. This study evaluated the pharmacokinetic, anti-inflammatory, and safety profile of minocycline after intracerebral hemorrhage.

Methods: This study was a single-site, randomized controlled trial of minocycline conducted from 2013 to 2016. Adults ≥18 years with primary intracerebral hemorrhage who could have study drug administered within 24 hours of onset were included. Patients received 400 mg of intravenous minocycline, followed by 400 mg minocycline oral daily for 4 days. Serum concentrations of minocycline after the last oral dose and biomarkers were sampled to determine the peak concentration, half-life, and anti-inflammatory profile.

Results: A total of 16 consecutive eligible patients were enrolled, with 8 randomized to minocycline. Although the literature supports a time to peak concentration (T) of 1 hour for oral minocycline, the T was estimated to be at least 6 hours in this cohort. The elimination half-life (available on 7 patients) was 17.5 hours (SD±3.5). No differences were observed in inflammatory biomarkers, hematoma volume, or perihematomal edema. Concentrations remained at neuroprotective levels (>3 mg/L) throughout the dosing interval in 5 of 7 patients.

Conclusions: In intracerebral hemorrhage, a 400 mg dose of minocycline was safe and achieved neuroprotective serum concentrations. However, oral administration led to delayed absorption in these critically ill patients and should not be used when rapid, high concentrations are desired. Given the safety and pharmacokinetic profile of minocycline in intracerebral hemorrhage and promising data in the treatment of ischemic stroke, intravenous minocycline is an excellent candidate for a prehospital treatment trial.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01805895.
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http://dx.doi.org/10.1161/STROKEAHA.117.018658DOI Listing
October 2017