Protective effects of primary neural stem cell treatment in ischemic stroke models

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

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Abstract WMP42: Neuro and Gliogenesis in a Nonhuman Primate Model of Ischemic Stroke with Impaired Dexterous Movements

Stroke ◽

10.1161/str.48.suppl_1.wmp42 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Gourav Choudhury ◽

Marcel Daadi

Keyword(s):

Stem Cell ◽

Ischemic Stroke ◽

Upper Extremity ◽

Neural Stem Cell ◽

Ischemia Reperfusion ◽

Stroke Recovery ◽

Fine Motor ◽

Retrieval Task ◽

Cell Compartment ◽

Stem Cell Compartment

Ischemic stroke is the leading cause of upper extremity motor impairments. Well-characterized experimental stroke models for upper extremity motor impairment remain underdeveloped. Cortical representation of dexterous movements in nonhuman primates (NHP) is functionally and topographically similar to that in humans. We recently reported the characterization of an NHP model of focal ischemia reperfusion with a defined syndrome, impaired arm function and finger dexterity. In this study, we investigated the cellular changes in the neural stem cell compartment and glial cell populations in this NHP model. NHPs were subjected to transient cerebral ischemia by temporarily occluding the M3 segment of the left side middle cerebral artery (MCA). Motor and cognitive functions following the stroke were evaluated using the object retrieval task with barrier-detour. Postmortem analysis included magnetic resonance imaging (MRI) and immunohistopathology to map the infarct and characterize the neurogenic and gliogenic changes. The MCA occlusion produced significant loss of fine motor function characterized by impaired dexterity. Immunocytochemical analysis revealed significant increase of Sox2+ neural stem cells in the subventricular zone, and of GFAP+ astrocytes (P<0.0001) and Iba-1+ microglia (P<0.0001) in the infarct region. In addition, there was a 42% increase in doublecortin positive cells (P<0.0001) compared to non-ischemic hemisphere. This study describes the cellular composition of the endogenous changes in the neural stem cell compartment and in the stroke region. These data may help reveal the cellular identity mediating neural plasticity and the cellular mechanisms mediating behavioral deficits and post-stroke recovery.

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Protective Effects of Preactivated and Disaggregated Shape-Changed Platelets and Human Embryonic Stem Cell-Derived Exosomes Improve Neurological Function and Attenuate Brain Infarct after Acute Ischemic Stroke

Neuropsychiatry ◽

10.4172/neuropsychiatry.1000308 ◽

2017 ◽

Vol 07 (06) ◽

Author(s):

Yi Ling Chen ◽

Yuan Ping Lin ◽

Sung Pei Hsun ◽

Pei Lin Shao ◽

Hon Kan Yip ◽

...

Keyword(s):

Stem Cell ◽

Ischemic Stroke ◽

Embryonic Stem Cell ◽

Acute Ischemic Stroke ◽

Human Embryonic Stem Cell ◽

Embryonic Stem ◽

Neurological Function ◽

Protective Effects ◽

Brain Infarct

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Protective Effects of Xenon on Propofol-Induced Neurotoxicity in Human Neural Stem Cell-Derived Models

Molecular Neurobiology ◽

10.1007/s12035-019-01769-5 ◽

2019 ◽

Vol 57 (1) ◽

pp. 200-207 ◽

Cited By ~ 1

Author(s):

Fang Liu ◽

Shuliang Liu ◽

Tucker A. Patterson ◽

Charles Fogle ◽

Joseph P. Hanig ◽

...

Keyword(s):

Stem Cell ◽

Neural Stem Cell ◽

Protective Effects ◽

Human Neural Stem Cell

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

Translational Stroke Research ◽

10.1007/s12975-019-00753-4 ◽

2019 ◽

Vol 11 (4) ◽

pp. 776-788 ◽

Cited By ~ 5

Author(s):

Samantha E. Spellicy ◽

Erin E. Kaiser ◽

Michael M. Bowler ◽

Brian J. Jurgielewicz ◽

Robin L. Webb ◽

...

Keyword(s):

Stem Cell ◽

Ischemic Stroke ◽

Functional Outcome ◽

Neural Stem Cell ◽

Functional Outcomes ◽

Extracellular Vesicle ◽

Stroke Model ◽

Midline Shift ◽

Post Stroke ◽

Non Invasive

AbstractMagnetic 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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Neural stem cell transplantation in ischemic stroke: A role for preconditioning and cellular engineering

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17700432 ◽

2017 ◽

Vol 37 (7) ◽

pp. 2314-2319 ◽

Cited By ~ 43

Author(s):

Joshua D Bernstock ◽

Luca Peruzzotti-Jametti ◽

Daniel Ye ◽

Florian A Gessler ◽

Dragan Maric ◽

...

Keyword(s):

Stem Cell ◽

Ischemic Stroke ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Neural Stem Cell ◽

Clinical Translation ◽

Ischemic Brain ◽

Cellular Therapies ◽

Beneficial Effects ◽

The World

Ischemic stroke continues to be a leading cause of morbidity and mortality throughout the world. To protect and/or repair the ischemic brain, a multitiered approach may be centered on neural stem cell (NSC) transplantation. Transplanted NSCs exert beneficial effects not only via structural replacement, but also via immunomodulatory and/or neurotrophic actions. Unfortunately, the clinical translation of such promising therapies remains elusive, in part due to their limited persistence/survivability within the hostile ischemic microenvironment. Herein, we discuss current approaches for the development of NSCs more amenable to survival within the ischemic brain as a tool for future cellular therapies in stroke.

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