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      Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model

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          Abstract

          Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metabolism in the infarcted tissue. The observed tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients.

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          Inflammatory mechanisms in ischemic stroke: therapeutic approaches

          Shaheen E Lakhan, Annette Kirchgessner, Magdalena Hofer (2009)
          Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.
          Article 0 comments Cited 322 times – based on 0 reviews     Review now
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            The biphasic function of microglia in ischemic stroke.

            Yuanyuan Ma, Jixian Wang, Yongting Wang … (2017)
            Microglia are brain resident macrophages originated from primitive progenitor cells in the yolk sac. Microglia can be activated within hours and recruited to the lesion site. Traditionally, microglia activation is considered to play a deleterious role in ischemic stroke, as inhibition of microglia activation attenuates ischemia induced brain injury. However, increasing evidence show that microglia activation is critical for attenuating neuronal apoptosis, enhancing neurogenesis, and promoting functional recovery after cerebral ischemia. Differential polarization of microglia could likely explain the biphasic role of microglia in ischemia. We comprehensively reviewed the mechanisms involved in regulating microglia activation and polarization. The latest discoveries of microRNAs in modulating microglia function are discussed. In addition, the interaction between microglia and other cells including neurons, astrocytes, oligodendrocytes, and stem cells were also reviewed. Future therapies targeting microglia may not exclusively aim at suppressing microglia activation, but also at modulating microglia polarization at different stages of ischemic stroke. More work is needed to elucidate the cellular and molecular mechanisms of microglia polarization under ischemic environment. The roles of microRNAs and transplanted stem cells in mediating microglia activation and polarization during brain ischemia also need to be further studied.
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              Recommendations for standards regarding preclinical neuroprotective and restorative drug development.

              (1999)
              The plethora of failed clinical trials with neuroprotective drugs for acute ischemic stroke have raised justifiable concerns about how best to proceed for the future development of such interventions. Preclinical testing of neuroprotective drugs is an important aspect of assessing their therapeutic potential, but guidelines concerning how to perform preclinical development of purported neuroprotective drugs for acute ischemic stroke are lacking. This conference of academicians and industry representatives was convened to suggest such guidelines for the preclinical evaluation of neuroprotective drugs and to recommend to potential clinical investigators the data they should review to reassure themselves that a particular neuroprotective drug has a reasonable chance to succeed in an appropriately designed clinical trial. Without rigorous, robust, and detailed preclinical evaluation, it is unlikely that novel neuroprotective drugs will prove to be effective when tested in large, time-consuming, and expensive clinical trials. Additionally, similar recommendations are provided for drugs with the potential to enhance recovery after acute ischemic stroke, a burgeoning new field with great potential but little currently available data. The suggestions contained in this document are meant to serve as overall guidelines that must be adapted to the individual characteristics related to particular drugs and their preclinical and clinical development needs.
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                Author and article information

                Contributors
                Franklin D. West: westf@uga.edu
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 30 August 2017
                Publication date PMC-release: 30 August 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 10075
                Affiliations
                [1 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Regenerative Bioscience Center, , University of Georgia, ; Athens, GA 30602 USA
                [2 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Department of Animal and Dairy Science, , University of Georgia, ; Athens, GA 30602 USA
                [3 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Department of Small Animal Medicine and Surgery, , University of Georgia, ; Athens, GA 30602 USA
                [4 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Department of Veterinary Biosciences & Diagnostic Imaging, , University of Georgia, ; Athens, GA 30602 USA
                [5 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Radiology and Imaging Sciences, , Emory University, ; Atlanta, GA 30329 USA
                [6 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Department of Pathology, , University of Georgia, ; Athens, GA 30602 USA
                [7 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Neurology, , Augusta University, ; Augusta, GA 30912 USA
                Article
                Publisher ID: 10406
                DOI: 10.1038/s41598-017-10406-x
                PMC ID: 5577218
                PubMed ID: 28855627
                SO-VID: a8bdbc1f-d22a-418f-bd21-d2ab0064762b
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 27 April 2017
                Date accepted : 7 August 2017
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2017

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